Diarylamine-containing compounds and compositions, and their use as modulators of c-kit receptors

ABSTRACT

Described herein are compounds that include a diarylamine structural feature. Also described herein are methods for making such compounds, methods for using such compounds to modulate the activity of c-kit receptors, and pharmaceutical compositions and medicaments comprising such compounds. Also described herein are methods of using such compounds, pharmaceutical compositions and medicaments to treat and/or prevent and/or inhibit and/or ameliorate the pathology and/or symptomology diseases or conditions associated with the activity of c-kit receptors.

CROSS-REFERENCE

This application claims the benefit of provisional application Ser. No.60/721,015 filed Sep. 27, 2005.

FIELD OF THE INVENTION

Compounds, methods of making such compounds, pharmaceutical compositionsand medicaments comprising such compounds, and methods of using suchcompounds to treat or prevent diseases or conditions associated withc-kit receptor activity are described.

BACKGROUND OF THE INVENTION

The c-kit gene encodes a receptor tyrosine kinase and the ligand for thec-kit receptor is called the stem cell factor (SCF), which is theprincipal growth factor for mast cells. The activity of the c-kitreceptor protein tyrosine kinase is regulated in normal cells, and thenormal functional activity of the c-kit gene product is essential formaintenance of normal hematopoeisis, melanogenesis, genetogensis, andgrowth and differentiation of mast cells. Mutations that causeconstitutive activation of c-kit kinase activity in the absence of SCFbinding are implicated in various diseases including malignant humancancers.

SUMMARY OF THE INVENTION

In one aspect are compounds having a diarylamine structure. In anotheraspect is the method of using such compounds having a diarylaminestructure for the modulation of a c-kit receptor.

In another aspect is the use of such compounds having a diarylaminestructure in the treatment of a disease or condition, or to produce amedicament for the treatment of a disease or condition, in whichmodulation of c-kit receptor activity can prevent, inhibit or amelioratethe pathology and/or symptoms of the disease or condition. In further oralternative embodiments, such diarylamine compounds comprise at leastone heterocycle group. In further or alternative embodiments, suchheterocycle groups contain at least one nitrogen. In further oralternative embodiments, such heterocycle groups are pyrimidines. Infurther or alternative embodiments, such diarylamines further comprisemulticyclic aryl groups. In further or alternative embodiments, suchdiarylamines further comprise at least one tricyclic aryl groups. Infurther or alternative embodiments, such diarylamines further compriseat least one bicyclic aryl groups. In further or alternativeembodiments, such diarylamines further comprise at least one monocyclicaryl groups. In further or alternative embodiments, the multicyclic arylgroups comprise at least one heterocycle. In further or alternativeembodiments, the tricyclic aryl groups comprise at least oneheterocycle. In further or alternative embodiments, the bicyclic arylgroups comprise at least one heterocycle. In further or alternativeembodiments, the monocyclic aryl group is a heterocycle.

In another aspect are pharmaceutical compositions comprising such acompound having a diarylamine structure. In further or alternativeembodiments, such diarylamine compounds comprise at least oneheterocycle group. In further or alternative embodiments, suchheterocycle groups contain at least one nitrogen. In further oralternative embodiments, such heterocycle groups are pyrimidines. Infurther or alternative embodiments, such diarylamines further comprisemulticyclic aryl groups. In further or alternative embodiments, suchdiarylamines further comprise at least one tricyclic aryl groups. Infurther or alternative embodiments, such diarylamines further compriseat least one bicyclic aryl groups. In further or alternativeembodiments, such diarylamines further comprise at least one monocyclicaryl groups. In further or alternative embodiments, the multicyclic arylgroups comprise at least one heterocycle. In further or alternativeembodiments, the tricyclic aryl groups comprise at least oneheterocycle. In further or alternative embodiments, the bicyclic arylgroups comprise at least one heterocycle. In further or alternativeembodiments, the monocyclic aryl group is a heterocycle.

In another aspect are methods for making such compounds having adiarylamine structure. In further or alternative embodiments, suchdiarylamine compounds comprise at least one heterocycle group. Infurther or alternative embodiments, such heterocycle groups contain atleast one nitrogen. In further or alternative embodiments, suchheterocycle groups are pyrimidines. In further or alternativeembodiments, such diarylamines further comprise multicyclic aryl groups.In further or alternative embodiments, such diarylamines furthercomprise at least one tricyclic aryl groups. In further or alternativeembodiments, such diarylamines further comprise at least one bicyclicaryl groups. In further or alternative embodiments, such diarylaminesfurther comprise at least one monocyclic aryl groups. In further oralternative embodiments, the multicyclic aryl groups comprise at leastone heterocycle. In further or alternative embodiments, the tricyclicaryl groups comprise at least one heterocycle. In further or alternativeembodiments, the bicyclic aryl groups comprise at least one heterocycle.In further or alternative embodiments, the monocyclic aryl group is aheterocycle.

In another aspect are compounds having the structure of Formula (A) orFormula (B):

wherein:

-   -   Q₁ is H, halogen, a group comprising a non-aromatic tertiary        amine, a group comprising a non-aromatic secondary amine, or is        an optionally substituted moiety selected from the group        consisting of: -L-alkyl, -L-cycloalkyl, -L-heteroalkyl,        -L-haloalkyl, -L-aryl, -L-heterocycloalkyl, and -L-heteroaryl;        wherein L is selected from a bond, —O—, —NH—, —S—, —C(O)—,        —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″YC(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y is optionally substituted        arylene or heteroarylene;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y¹ is optionally        substituted arylene or heteroarylene;    -   Q₂ is selected from the group consisting of H, halogen, and a        group comprising an optionally substituted moiety selected from        -L₆-alkyl, -L₆-cycloalkyl, -L₆-heteroalkyl, -L₆-haloalkyl,        -L₆-aromatic carbocycle, -L₆-heterocycloalkyl, and -L₆-aromatic        heterocycle; wherein L₆ is selected from a bond, —O—, —NH—, —S—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,        —C(O)—NR″Y″C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y″ is        optionally substituted arylene or heteroarylene;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   any two R₁ groups together may form an optionally substituted 5        to 8-membered heterocyclic, cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl, wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, Q₁ is selected from the groupconsisting of H, halogen, and an optionally substituted moiety selectedfrom -L-alkyl, -L-cycloalkyl, -L-heteroalkyl, -L-haloalkyl, -L-aryl,-L-heterocycloalkyl, and -L-heteroaryl; wherein L is selected from abond, —O—, —S—, and, —C(O)O—; wherein said optional substituents areselected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl.

In further or alternative embodiments, Q₁ is an optionally substitutedmoiety selected from -L-alkyl, -L-heteroalkyl, and -L-heterocycloalkyl;wherein L is selected from a bond, —O—, —S—, and, —C(O)O—; wherein saidoptional substituents are selected from halogen, OH, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, andheteroaryl.

In further or alternative embodiments, Q₁ is -L-R, wherein R is a groupcomprising a tertiary amine and L is optionally substituted and selectedfrom a bond, —O—, —S—, and, —C(O)O—; wherein said optional substituentsare selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl.

In further or alternative embodiments, Q₂ is an optionally substitutedmoiety selected from, -L₆-cycloalkyl, -L₆-aromatic carbocycle,-L₆-heterocycloalkyl, and -L₆-aromatic heterocycle; wherein L₆ isselected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—; wherein said optional substituents are selected from halogen,OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,haloaryl, and heteroaryl.

In further or alternative embodiments, Q₂ is selected from the groupconsisting of an optionally substituted cycloalkyl, optionallysubstituted aromatic carbocycle, optionally substitutedheterocycloalkyl, and optionally substituted aromatic heterocycle;wherein said optional substituents are selected from halogen, OH,C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl,and heteroaryl.

In another aspect are compounds having the structure of Formula (1) orFormula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R1 groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments are compounds having the structureof Formula (1) or Formula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted phenyl;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₁ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of hydrogen and        C₁₋₆alkyl;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, the Ar is a group comprising asubstituted, optionally further substituted six-membered aromaticheterocycle. In further or alternative embodiments, said optionalsubstituents are selected from halogen, OH, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl.

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) or Formula (46) is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, the compound is selected from thegroup consisting of: tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylaminopyrimidin-5-yl)benzylamino)acetate,2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid, tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,tert-butyl2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,tert-butyl2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenylacetate, ethyl2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,methyl4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoicacid, methyl2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,tert-butyl3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylicacid,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoicacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylicacid, ethyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)aceticacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylicacid, 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylmorpholine-4-carboxylate,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate,4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)aceticacid, methyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoicacid,(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylicacid,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylicacid,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,methyl4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide,and(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(B) is selected from the group consisting of

—CH₂OH, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(E) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, R₅ is H. In further oralternative embodiments, each R₁ is H. In further or alternativeembodiments, each R₁ is H and R₅ is H. In further or alternativeembodiments, Q is a group comprising a non-aromatic tertiary amine.

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (1) are selected from Formula (2), Formula (3),or Formula (44):

wherein:

-   -   M is selected from the group consisting of H, OH, SH, NO₂, CN,        NR″₂, and an optionally substituted moiety selected from        -L₇-alkyl, -L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl,        -L₇-aryl, -L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—, —CR″₂NR″WO—,        —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ is        optionally substituted arylene or optionally substituted        heteroarylene; wherein said optional substituents are selected        from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and        halo-C₁₋₆alkoxy; provided that M is not H in Formula (2);    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   each X is independently selected from N or CR₂, provided that at        least one but no more than 2X groups are N;    -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂ is        selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—,        —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—,        —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein        said optional substituents are selected from halogen, OH,        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, L₇ is selected from a bond, —O—,—NH—, —S—, —C(O)—, —C(S)—, —OC(O)—, —CH₂NHCH₂C(O)O—, —CH₂NH(CH₂)₂O—,—C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—. In further or alternative embodiments,L₂ is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. Infurther or alternative embodiments, each R₁ is H. In further oralternative embodiments, each R₂ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH, each R₂ is H, and R₅ is H.

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (46) are selected from Formula (47), Formula(48), or Formula (49):

wherein:

-   -   M is selected from the group consisting of H, OH, SH, NO₂, CN,        NR″₂, and an optionally substituted moiety selected from        -L₇-alkyl, -L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl,        -L₇-aryl, -L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—, —CR″₂NR″WO—,        —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ is        optionally substituted arylene or optionally substituted        heteroarylene; wherein said optional substituents are selected        from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and        halo-C₁₋₆alkoxy; provided that M is not H in Formula (47);    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   each X is independently selected from N or CR₂, provided that at        least one but no more than 2X groups are N;    -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR′C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, L₇ is selected from a bond, —O—,—NH—, —S—, —C(O)—, —C(S)—, —OC(O)—, —CH₂NHCH₂C(O)O—, —CH₂NH(CH₂)₂O—,—C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—. In further or alternative embodiments,L₂ is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. Infurther or alternative embodiments, each R₁ is H. In further oralternative embodiments, each R₂ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH, each R₂ is H, and R₅ is H.

In a further or alternative embodiment of this aspect, are compoundshaving the structure of Formula (1) or Formula (46) in which the Argroup is a 5-membered carbocyclic bearing up to four substituents. Infurther or alternative embodiments, compounds having the structure ofFormula (1) are selected from Formula (4), Formula (5), or Formula (6):

wherein:

-   -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 7-membered heterocyclic, cycloalkyl, or aryl        ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, L₂ is selected from a bond,—C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,—C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. In further oralternative embodiments, each R₁ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH and R₅ is H. In further or alternative embodiments of Formulas (4),(5), or (6), Q is at the meta position corresponding to Formula (46).

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (1) are selected from the group consisting of:

wherein;

-   -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₂ groups together may form an optionally        substituted 6 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, L₂ is selected from a bond,—C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,—C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—. In further oralternative embodiments, each R₁ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH and R₅ is H. In further or alternative embodiments of Formulas(7)-(22), or (53), Q is at the meta position corresponding to Formula(46).

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments of this aspect, Q is

wherein R_(B) is selected from the group consisting of

—CH₂OH, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments of this aspect, Q is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂.

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

wherein each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments of this aspect, Q is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(E) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

In further or alternative embodiments of this aspect, Q is selected fromthe group consisting of

In further or alternative embodiments, R₅ is H. In further oralternative embodiments, each R₁ is H. In further or alternativeembodiments, each R₁ is H and R₅ is H. In further or alternativeembodiments, Q is a group comprising a non-aromatic tertiary amine.

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (1) are selected from Formula (23), Formula(24), or Formula (45):

wherein:

-   -   M is selected from the group consisting of H, OH, SH, NO₂, CN,        NR″₂, and an optionally substituted moiety selected from        -L₇-alkyl, -L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl,        -L₇-aryl, -L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—, —CR″₂NR″WO—,        —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ is        optionally substituted arylene or optionally substituted        heteroarylene; wherein said optional substituents are selected        from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and        halo-C₁₋₆alkoxy; provided that M is not H in Formula (23);    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   each X is independently selected from N or CR₂, provided that at        least one but no more than 2X groups are N;    -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, and halo-C₁₋₆alkoxy;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   each of R₃ and R₄ is independently an optionally substituted        moiety selected from -Z, -L₃-Z, -L₃-H, -L₃-alkyl,        -L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,        -L₃-heterocycloalkyl, and -L₃-heteroaryl; wherein L₃ is selected        from a bond, —C(S)—, —C(O)O—, —C(O)NR′″—, —(CR″₂)₁₋₆—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, —CR′″₂S(O)NR′″—, —CR′″₂C(O)NR′″—,        —(CR′″₂)₁₋₆NR′″—, —(CR″₂)₁₋₆O—, —(CR′″₂)₁₋₆C(O)O—, —Y²C(O)O—,        and an optionally substituted C₁₋₆alkylene;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆C(O)OR₆, —C(O)NR′″₂, —C(O)R₆, or —C(O)OR₆;        -   Y² is an optionally substituted cycloalkyl ring or            optionally substituted non-aromatic heterocyclic ring;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Y³ is optionally substituted aryl, optionally substituted            heteroaryl, optionally substituted cycloalkyl, or optionally            substituted non-aromatic heterocycle;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Z is —H, —OH, —CN, —COOR′″, —NR′″2, or —C≡CR′″;        -   each R′″ is independently H, alkyl, or substituted alkyl;        -   or two R′″ together may form a 3-6 membered cycloalkyl or            heterocyclic ring;    -   or R₃ and R₄ taken together with the N atom to which they are        attached may form an optionally substituted 3 to 8-membered        heterocyclic ring;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆Y⁴, —(CR′″₂)₁₋₆OR₆, —C(O)NR′″R₆, —C(O)OR₆, —OR₆,            —NR′″C(O)OR₆, —NR′″C(O)R₆, —(CR′″₂)₁₋₆C(O)OR₆,            —(CR′″₂)₁₋₆NR′″C(O)OR₆, —(CR′″₂)₁₋₆NR₇R₈, —S(O)₂NR′″2,            —C(O)R₆, —OC(O)R₆, —NR₇R₉, —(CR′″₂)₁₋₆C(O)NR₇R₈,            —S(O)₂R_(A), or —C(O)R_(A);        -   Y⁴ is aryl, heteroaryl, cycloalkyl, or non-aromatic            heterocycle;        -   R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH;        -   R₆ is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic            heterocycle, aryl, or heteroaryl;        -   each of R₇ and R₈ is independently H, OH, halogen,            C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, or halo-C₁₋₆alkoxy;        -   or R₇ and R₈ taken together with the N atom to which they            are attached may form a 3 to 6-membered heterocyclic ring;    -   T₁ is an optionally substituted moiety selected from -L₄-,        -alkylene-L₄-, -L₄-alkylene-, -L₄-cycloalkylene-,        -L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,        -L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is        selected from a bond, —O—, —NH—, —S—, —CR″₂—, —NR′″C(O)—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR′″(CR″₂)₁₋₆C(O)O—, —C(O)NR′″(CR″₂)₁₋₆C(O)—,        —CR″₂NR′″CR″₂C(O)O—, —C(O)NR′″NR′″C(O)O—, —C(O)NR′″(CR″₂)₁₋₆—,        —CR″₂C(O)—, and —S(O)NH—;        -   wherein said optional substituents are selected from            halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,            halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl;            or a pharmaceutically acceptable salt, pharmaceutically            acceptable N-oxide, pharmaceutically active metabolite,            pharmaceutically acceptable prodrug, or pharmaceutically            acceptable solvate thereof.

In further or alternative embodiments, L₇ is selected from a bond, —O—,—NH—, —S—, —C(O)—, —C(S)—, —OC(O)—, —CH₂NHCH₂C(O)O—, —CH₂NH(CH₂)₂O—,—C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—. In further or alternative embodiments,L₂ is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—.

In further or alternative embodiments, each of R₃ and R₄ isindependently an optionally substituted moiety selected from -L₃-alkyl,-L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,-L₃-heterocycloalkyl, and -L₃-heteroaryl;

-   -   wherein L₃ is selected from a bond, —C(S)—, —C(O)O—, —C(O)NH—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, and —CR′″₂S(O)NH—; wherein said        optional substituents are selected from halogen, OH, C₁₋₆alkyl,        C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, and        heteroaryl;    -   or R₃ and R₄ together may form an optionally substituted 3 to        8-membered heterocyclic ring; wherein said optional substituents        are selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, heteroaryl.

In further or alternative embodiments, T₁ is an optionally substitutedmoiety selected from -L₄-alkylene-, -L₄-cycloalkylene-,-L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,-L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is selectedfrom a bond, —O—, —NH—, —S—, —CR″₂—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—.

In further or alternative embodiments, each R₁ is H. In further oralternative embodiments, each R₂ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH, each R₂ is H, and R₅ is H.

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (46) are selected from Formula (50), Formula(51), or Formula (52):

wherein:

-   -   M is selected from the group consisting of H, OH, SH, NO₂, CN,        NR″₂, and an optionally substituted moiety selected from        -L₇-alkyl, -L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl,        -L₇-aryl, -L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—, —CR″₂NR″WO—,        —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ is        optionally substituted arylene or optionally substituted        heteroarylene; wherein said optional substituents are selected        from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and        halo-C₁₋₆alkoxy; provided that M is not H in Formula (50);    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   each X is independently selected from N or CR₂, provided that at        least one but no more than 2X groups are N;    -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, and halo-C₁₋₆alkoxy;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   each of R₃ and R₄ is independently an optionally substituted        moiety selected from -Z, -L₃-Z, -L₃-H, -L₃-alkyl,        -L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,        -L₃-heterocycloalkyl, and -L₃-heteroaryl; wherein L₃ is selected        from a bond, —C(S)—, —C(O)O—, —C(O)NR′″—, —(CR″₂)₁₋₆—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, —CR′″₂S(O)NR′″—, —CR′″₂C(O)NR′″—,        —(CR′″₂)₁₋₆NR′″—, —(CR′″₂)₁₋₆O—, —(CR′″₂)₁₋₆C(O)O—, —Y²C(O)O—,        and an optionally substituted C₁₋₆alkylene;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆C(O)OR₆, —C(O)NR′″₂, —C(O)R₆, or —C(O)OR₆;        -   Y² is an optionally substituted cycloalkyl ring or            optionally substituted non-aromatic heterocyclic ring;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Y³ is optionally substituted aryl, optionally substituted            heteroaryl, optionally substituted cycloalkyl, or optionally            substituted non-aromatic heterocycle;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Z is —H, —OH, —CN, —COOR′″, —NR′″2, or —C≡CR′″;        -   each R′″ is independently H, alkyl, or substituted alkyl;        -   or two R′″ together may form a 3-6 membered cycloalkyl or            heterocyclic ring;    -   or R₃ and R₄ taken together with the N atom to which they are        attached may form an optionally substituted 3 to 8-membered        heterocyclic ring;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆Y⁴, —(CR′″₂)₁₋₆OR₆, —C(O)NR′″R₆, —C(O)OR₆, —OR₆,            —NR′″C(O)OR₆, —NR′″C(O)R₆, —(CR′″₂)₁₋₆C(O)OR₆,            —(CR′″₂)₁₋₆NR′″C(O)OR₆, —(CR′″₂)₁₋₆NR₇R₈, —S(O)₂NR′″2,            —C(O)R₆, —OC(O)R₆, —NR₇R₈, —(CR′″2)₁₋₆C(O)NR₇R₈,            —S(O)₂R_(A), or —C(O)R_(A);        -   Y⁴ is aryl, heteroaryl, cycloalkyl, or non-aromatic            heterocycle;        -   R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH;        -   R₆ is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic            heterocycle, aryl, or heteroaryl;        -   each of R₇ and R₈ is independently H, OH, halogen,            C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, or halo-C₁₋₆alkoxy;        -   or R₇ and R₈ taken together with the N atom to which they            are attached may form a 3 to 6-membered heterocyclic ring;    -   T₁ is an optionally substituted moiety selected from -L₄-,        -alkylene-L₄-, -L₄-alkylene-, -L₄-cycloalkylene-,        -L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,        -L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is        selected from a bond, —O—, —NH—, —S—, —CR″₂—, —NR′″C(O)—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR′″(CR″₂)₁₋₆C(O)O—, —C(O)NR′″(CR″₂)₁₋₆C(O)—,        —CR″₂NR′″CR″₂C(O)O—, —C(O)NR′″NR′″C(O)O—, —C(O)NR′″(CR″₂)₁₋₆—,        —CR″₂C(O)—, and —S(O)NH—;        -   wherein said optional substituents are selected from            halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,            halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl;            or a pharmaceutically acceptable salt, pharmaceutically            acceptable N-oxide, pharmaceutically active metabolite,            pharmaceutically acceptable prodrug, or pharmaceutically            acceptable solvate thereof.

In further or alternative embodiments, L₇ is selected from a bond, —O—,—NH—, —S—, —C(O)—, —C(S)—, —OC(O)—, —CH₂NHCH₂C(O)O—, —CH₂NH(CH₂)₂O—,—C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—. In further or alternative embodiments,L₂ is selected from a bond, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—.

In further or alternative embodiments, each of R₃ and R₄ isindependently an optionally substituted moiety selected from -L₃-alkyl,-L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,-L₃-heterocycloalkyl, and -L₃-heteroaryl;

-   -   wherein L₃ is selected from a bond, —C(S)—, —C(O)O—, —C(O)NH—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, and —CR′″₂S(O)NH—; wherein said        optional substituents are selected from halogen, OH, C₁₋₆alkyl,        C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, and        heteroaryl;    -   or R₃ and R₄ together may form an optionally substituted 3 to        8-membered heterocyclic ring; wherein said optional substituents        are selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, heteroaryl.

In further or alternative embodiments, T₁ is an optionally substitutedmoiety selected from -L₄-alkylene-, -L₄-cycloalkylene-,-L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,-L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is selectedfrom a bond, —O—, —NH—, —S—, —CR″₂—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—.

In further or alternative embodiments, each R₁ is H. In further oralternative embodiments, each R₂ is H. In further or alternativeembodiments, R₅ is H. In further or alternative embodiments, each R₁ isH, each R₂ is H, and R₅ is H.

In a further or alternative embodiment of this aspect, compounds havingthe structure of Formula (1) are selected from Formula (25), Formula(26), or Formula (27):

wherein;

-   -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   each of R₃ and R₄ is independently an optionally substituted        moiety selected from -Z, -L₃-Z, -L₃-H, -L₃-alkyl,        -L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,        -L₃-heterocycloalkyl, and -L₃-heteroaryl; wherein L₃ is selected        from a bond, —C(S)—, —C(O)O—, —C(O)NR′″—, —CR′″₂S(O)—,        —CR′″₂S(O)₂—, —CR′″₂S(O)NR′″—, —CR′″₂C(O)NR′″—,        —(CR′″₂)₁₋₆NR′″—, —(CR′″₂)₁₋₆O—, —(CR′″₂)₁₋₆C(O)O—, —Y²C(O)O—,        and an optionally substituted C₁₋₆alkylene;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆C(O)OR₆, —C(O)NR′″₂, —C(O)R₆, or —C(O)OR₆;        -   Y² is an optionally substituted cycloalkyl ring or            optionally substituted non-aromatic heterocyclic ring;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Y³ is optionally substituted aryl, optionally substituted            heteroaryl, optionally substituted cycloalkyl, or optionally            substituted non-aromatic heterocycle;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Z is —H, —OH, —CN, —COOR′″, —NR′″2, or —C≡CR′″;        -   each R′″ is independently H, alkyl, or substituted alkyl;        -   or two R′″ together may form a 3-6 membered cycloalkyl or            heterocyclic ring;    -   or R₃ and R₄ taken together with the N atom to which they are        attached may form an optionally substituted 3 to 8-membered        heterocyclic ring;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆Y⁴, —(CR′″₂)₁₋₆OR₆, —C(O)NR′″R₆, —C(O)OR₆, —OR₆,            —NR′″C(O)OR₆, —NR′″C(O)R₆, —(CR′″₂)₁₋₆C(O)OR₆,            —(CR′″₂)₁₋₆NR′″C(O)OR₆, —(CR′″2)₁₋₆NR₇R₈, —S(O)₂NR′″2,            —C(O)R₆, —OC(O)R₆, —NR₇R₈, —(CR′″₂)₁₋₆C(O)NR₇R₈,            —S(O)₂R_(A), or —C(O)R_(A);        -   Y⁴ is aryl, heteroaryl, cycloalkyl, or non-aromatic            heterocycle;        -   R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH;        -   R₆ is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic            heterocycle, aryl, or heteroaryl;        -   each of R₇ and R₈ is independently H, OH, halogen,            C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, or halo-C₁₋₆alkoxy;        -   or R₇ and R₈ taken together with the N atom to which they            are attached may form a 3 to 6-membered heterocyclic ring;    -   T₁ is an optionally substituted moiety selected from -L₄-,        -alkylene-L₄-, -L₄-alkylene-, -L₄-cycloalkylene-,        -L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,        -L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is        selected from a bond, —O—, —NH—, —S—, —CR″₂—, —NR′″C(O)—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR′″(CR″₂)₁₋₆C(O)O—, —C(O)NR′″(CR″₂)₁₋₆C(O)—,        —CR″₂NR′″CR″₂C(O)O—, —C(O)NR′″NR′″C(O)O—, —C(O)NR′″(CR″₂)₁₋₆—,        —CR″₂C(O)—, and —S(O)NH—;        -   wherein said optional substituents are selected from            halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,            halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl;            or a pharmaceutically acceptable salt, pharmaceutically            acceptable N-oxide, pharmaceutically active metabolite,            pharmaceutically acceptable prodrug, or pharmaceutically            acceptable solvate thereof.

In further or alternative embodiments, L₂ is selected from a bond,—C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,—C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—.

In further or alternative embodiments, each of R₃ and R₄ isindependently an optionally substituted moiety selected from -L₃-alkyl,-L₃-cycloalkyl, -L₃-heteroalkyl, -L -haloalkyl, -L₃-aryl,-L₃-heterocycloalkyl, and -L₃-heteroaryl;

-   -   wherein L₃ is selected from a bond, —C(S)—, —C(O)O—, —C(O)NH—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, and —CR′″₂S(O)NH—; wherein said        optional substituents are selected from halogen, OH, C₁₋₆alkyl,        C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, and        heteroaryl;    -   or R₃ and R₄ together may form an optionally substituted 3 to        8-membered heterocyclic ring; wherein said optional substituents        are selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy,        halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, heteroaryl.

In further or alternative embodiments, T₁ is an optionally substitutedmoiety selected from -L₄-alkylene-, -L₄-cycloalkylene-,-L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,-L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is selectedfrom a bond, —O—, —NH—, —S—, —CR″ 2-, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—.

In further or alternative embodiments, each R₁ is H. In further oralternative embodiments, R₅ is H. In further or alternative embodiments,each R₁ is H and R₅ is H. In further or alternative embodiments ofFormulas (25), (26), or (27), -T₁NR₃R₄ is at the meta positioncorresponding to Formula (46).

In a further or alternative embodiment of this aspect, the compoundshaving the structure of Formula (1) are selected from the groupconsisting of:

wherein;

-   -   each R₂ is independently selected from the group consisting of        H, OH, halogen, and an optionally substituted moiety selected        from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,        -L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—;        wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₂ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   each of R₃ and R₄ is independently an optionally substituted        moiety selected from -Z, -L₃-Z, -L₃-H, -L₃-alkyl,        -L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,        -L₃-heterocycloalkyl, and -L₃-heteroaryl; wherein L₃ is selected        from a bond, —C(S)—, —C(O)O—, —C(O)NR′″—, —(CR″₂)₁₋₆—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, —CR′″₂S(O)NR′″—, —CR′″₂C(O)NR′″—,        —(CR′″₂)₁₋₆NR′″—, —(CR′″₂)₁₋₆O—, —(CR′″₂)₁₋₆C(O)O—, —Y²C(O)O—,        and an optionally substituted C₁₋₆alkylene;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆C(O)OR₆, —C(O)NR′″₂, —C(O)R₆, or —C(O)OR₆;        -   Y² is an optionally substituted cycloalkyl ring or            optionally substituted non-aromatic heterocyclic ring;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Y³ is optionally substituted aryl, optionally substituted            heteroaryl, optionally substituted cycloalkyl, or optionally            substituted non-aromatic heterocycle;            -   wherein said optional substituents are selected from                C₁₋₆alkyl, halogen, —OH, ═O, and —CN.        -   Z is —H, —OH, —CN, —COOR′″, —NR′″2, or —C≡CR′″;        -   each R′″ is independently H, alkyl, or substituted alkyl;        -   or two R′″ together may form a 3-6 membered cycloalkyl or            heterocyclic ring;    -   or R₃ and R₄ taken together with the N atom to which they are        attached may form an optionally substituted 3 to 8-membered        heterocyclic ring;        -   wherein said optional substituents are selected from            halogen, —OH, ═O, —Y³, C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH            substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,            —(CR′″₂)₁₋₆Y⁴, —(CR′″₂)₁₋₆OR₆, —C(O)NR′″R₆, —C(O)OR₆, —OR₆,            —NR′″C(O)OR₆, —NR′″C(O)R₆, —(CR′″₂)₁₋₆C(O)OR₆,            —(CR′″₂)₁₋₆NR′″C(O)OR₆, —(CR′″₂)₁₋₆NR₇R₉, —S(O)₂NR′″2,            —C(O)R₆, —OC(O)R₆, —NR₇R₈, —(CR′″₂)₁₋₆C(O)NR₇R₈,            —S(O)₂R_(A), or —C(O)R_(A);        -   Y⁴ is aryl, heteroaryl, cycloalkyl, or non-aromatic            heterocycle;        -   R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH;        -   R₆ is H, alkyl, substituted alkyl, cycloalkyl, non-aromatic            heterocycle, aryl, or heteroaryl;        -   each of R₇ and R₈ is independently H, OH, halogen,            C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, or halo-C₁₋₆alkoxy;        -   or R₇ and R₈ taken together with the N atom to which they            are attached may form a 3 to 6-membered heterocyclic ring;    -   T₁ is an optionally substituted moiety selected from -L₄-,        -alkylene-L₄-, -L₄-alkylene-, -L₄-cycloalkylene-,        -L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,        -L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is        selected from a bond, —O—, —NH—, —S—, —CR″₂—, —NR′″C(O)—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NR′″—, —S(O)—, —S(O)₂—, —OC(O)—,        C(O)NR′″(CR″₂)₁₋₆C(O)O—, —C(O)NR′″(CR″₂)₁₋₆C(O)—,        —CR″₂NR′″CR″₂C(O)O—, —C(O)NR′″NR′″C(O)O—, —C(O)NR′″(CR″₂)₁₋₆—,        —CR″₂C(O)—, and —S(O)NH—;        -   wherein said optional substituents are selected from            halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,            halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl;            or a pharmaceutically acceptable salt, pharmaceutically            acceptable N-oxide, pharmaceutically active metabolite,            pharmaceutically acceptable prodrug, or pharmaceutically            acceptable solvate thereof.

In further or alternative embodiments, L₂ is selected from a bond,—C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,—C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—.

In further or alternative embodiments, each of R₃ and R₄ isindependently an optionally substituted moiety selected from -L₃-alkyl,-L₃-cycloalkyl, -L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl,-L₃-heterocycloalkyl, and -L₃-heteroaryl;

-   -   wherein L₃ is selected from a bond, —C(S)—, —C(O)O—, —C(O)NH—,        —CR′″₂S(O)—, —CR′″₂S(O)₂—, and —CR′″₂S(O)NH—; wherein said        optional substituents are selected from halogen, OH, C₁₋₆alkyl,        C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, and        heteroaryl;    -   or R₃ and R₄ together may form an optionally substituted 3 to        8-membered heterocyclic ring;    -   wherein said optional substituents are selected from halogen,        OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy,        aryl, haloaryl, heteroaryl.

In further or alternative embodiments, T₁ is an optionally substitutedmoiety selected from -L₄-alkylene-, -L₄-cycloalkylene-,-L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,-L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is selectedfrom a bond, —O—, —NH—, —S—, —CR″₂—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—.

In further or alternative embodiments, each R₁ is H. In further oralternative embodiments, R₅ is H. In further or alternative embodiments,each R₁ is H and R₅ is H. In further or alternative embodiments ofFormulas (28)-(43), or (54), -T₁NR₃R₄ is at the meta positioncorresponding to Formula (46).

In another aspect is a method for modulating the activity of a c-kitkinase receptor comprising contacting the c-kit kinase receptor with acompound having the structure of Formula (A) or Formula (B):

wherein:

-   -   Q₁ is H, halogen, a group comprising a non-aromatic tertiary        amine, a group comprising a non-aromatic secondary amine, or is        an optionally substituted moiety selected from the group        consisting of: -L-alkyl, -L-cycloalkyl, -L-heteroalkyl,        -L-haloalkyl, -L-aryl, -L-heterocycloalkyl, and -L-heteroaryl;        wherein L is selected from a bond, —O—, —NH—, —S—, —C(O)—,        —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″YC(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y is optionally substituted        arylene or heteroarylene;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y¹ is optionally        substituted arylene or heteroarylene;    -   Q₂ is selected from the group consisting of H, halogen, and a        group comprising an optionally substituted moiety selected from        -L₆-alkyl, -L₆-cycloalkyl, -L₆-heteroalkyl, -L₆-haloalkyl,        -L₆-aromatic carbocycle, -L₆-heterocycloalkyl, and -L₆-aromatic        heterocycle; wherein L₆ is selected from a bond, —O—, —NH—, —S—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,        —C(O)—NR″Y″C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y″ is        optionally substituted arylene or heteroarylene;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   any two R₁ groups together may form an optionally substituted 5        to 8-membered heterocyclic, cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl, wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, Q₁ is selected from the groupconsisting of H, halogen, and an optionally substituted moiety selectedfrom -L-alkyl, -L-cycloalkyl, -L-heteroalkyl, -L-haloalkyl, -L-aryl,-L-heterocycloalkyl, and -L-heteroaryl; wherein L is selected from abond, —O—, —S—, and, —C(O)O—; wherein said optional substituents areselected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl.

In further or alternative embodiments, Q₁ is an optionally substitutedmoiety selected from -L-alkyl, -L-heteroalkyl, and -L-heterocycloalkyl;wherein L is selected from a bond, —O—, —S—, and, —C(O)O—; wherein saidoptional substituents are selected from halogen, OH, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, andheteroaryl.

In further or alternative embodiments, Q₁ is -L-R, wherein R is a groupcomprising a tertiary amine and L is optionally substituted and selectedfrom a bond, —O—, —S—, and, —C(O)O—; wherein said optional substituentsare selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, haloaryl, and heteroaryl.

In further or alternative embodiments, Q₂ is an optionally substitutedmoiety selected from, -L₆-cycloalkyl, -L₆-aromatic carbocycle,-L₆-heterocycloalkyl, and -L₆-aromatic heterocycle; wherein L₆ isselected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and—S(O)NH—; wherein said optional substituents are selected from halogen,OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,haloaryl, and heteroaryl.

In further or alternative embodiments, Q₂ is selected from the groupconsisting of an optionally substituted cycloalkyl, optionallysubstituted aromatic carbocycle, optionally substitutedheterocycloalkyl, and optionally substituted aromatic heterocycle;wherein said optional substituents are selected from halogen, OH,C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl,and heteroaryl.

In a further or alternative embodiment of this aspect, the compound ofFormula (A) or Formula (B) is a compound having the structure of Formula(1) or Formula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—,        —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R1 groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, the compound of Formula (A) orFormula (B), directly contacts the c-kit kinase receptor. In further oralternative embodiments, the contacting occurs in vitro. In further oralternative embodiments, the contacting occurs in vivo.

In further or alternative embodiments, the Ar is a group comprising asubstituted, optionally further substituted six-membered aromaticheterocycle. In further or alternative embodiments, said optionalsubstituents are selected from halogen, OH, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl. In further or alternative embodiments, the compound is thecompound of any of Formula (1) to Formula (54) in various embodimentsdescribed above.

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, the compound is selected from thegroup consisting of: tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzylamino)acetate,2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid, tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,tert-butyl2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,tert-butyl2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenylacetate, ethyl2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,methyl4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoicacid, methyl2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,tert-butyl3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylicacid,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoicacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylicacid, ethyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)aceticacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylicacid, 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylmorpholine-4-carboxylate,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate,4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)aceticacid, methyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoicacid,(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylicacid,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylicacid,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,methyl4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide,and(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(B) is selected from the group consisting of

—CH₂OH, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(B) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In another aspect is pharmaceutical compositions comprising at least onecompound having the structure of Formula (1) or Formula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl; or any two adjacent R₁ groups together        may form an optionally substituted 5 to 8-membered heterocyclic,        cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof, in admixture with one or more        suitable excipients.

In further or alternative embodiments, the one or more excipients aresuitable for parenteral administration. In further or alternativeembodiments, the one or more excipients are suitable for oraladministration.

In further or alternative embodiments, the Ar is a group comprising asubstituted, optionally further substituted six-membered aromaticheterocycle. In further or alternative embodiments, said optionalsubstituents are selected from halogen, OH, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl. In further or alternative embodiments, the compound is thecompound of any of Formula (1) to Formula (54) in various embodimentsdescribed above.

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, the compound is selected from thegroup consisting of: tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzylamino)acetate,2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid, tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,tert-butyl2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,tert-butyl2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenylacetate, ethyl2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,methyl4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoicacid, methyl2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,tert-butyl3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylicacid,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoicacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylicacid, ethyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)aceticacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylicacid, 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylmorpholine-4-carboxylate,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate,4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)aceticacid, methyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoicacid,(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylicacid,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylicacid,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,methyl4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide,and(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(B) is selected from the group consisting of

—CH₂OH, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(E) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In another aspect are methods of treating a disease or condition inanimals in which modulation of c-kit receptor activities can prevent,inhibit or ameliorate the pathology and/or symptomology of the diseaseor condition, which methods comprise administering to the animal atherapeutically effective amount of a compound having the structure ofFormula (A) or Formula (B):

wherein;

-   -   Q₁ is H, halogen, a group comprising a non-aromatic tertiary        amine, a group comprising a non-aromatic secondary amine, or is        an optionally substituted moiety selected from the group        consisting of: -L-alkyl, -L-cycloalkyl, -L-heteroalkyl,        -L-haloalkyl, -L-aryl, -L-heterocycloalkyl, and -L-heteroaryl;        wherein L is selected from a bond, —O—, —NH—, —S—, —C(O)—,        —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″YC(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y is optionally substituted        arylene or heteroarylene;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁ is        selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—,        —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—,        —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″Y¹C(O)O—, —C(O)NR″NR″C(O)O—, and        —S(O)NH—; and Y¹ is optionally substituted arylene or        heteroarylene;    -   Q₂ is selected from the group consisting of H, halogen, and a        group comprising an optionally substituted moiety selected from        -L₆-alkyl, -L₆-cycloalkyl, -L₆-heteroalkyl, -L₆-haloalkyl,        -L₆-aromatic carbocycle, -L₆-heterocycloalkyl, and -L₁-aromatic        heterocycle; wherein L₆ is selected from a bond, —O—, —NH—, —S—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,        —C(O)—NR″Y″C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y″ is        optionally substituted arylene or heteroarylene;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   any two R₁ groups together may form an optionally substituted 5        to 8-membered heterocyclic, cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl, wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In a further or alternative embodiment of this aspect, compounds ofFormula (A) or Formula (B) are compounds having the structure of Formula(1) or Formula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R₁ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₁-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In a further or alternative embodiment of this aspect, the methodfurther comprises administration of a therapeutically effective amountof a second substance, wherein the second substance is used in thetreatment of a disease or condition selected from the group consistingof a neoplastic disease, an allergy disease, an inflammatory disease, anautoimmume disease, a graft-versus-host disease, a metabolic syndrome, aCNS related disorders, a neurodegenerative disease, a pain condition, asubstance abuse disorder, a prion disease, a cancer, a heart disease, afibrotic disease, idiopathic pulmonary arterial hypertension (IPAH), andprimary pulmonary hypertension (PPH).

In further or alternative embodiments, the second substance is selectedfrom the group consisting of a bronchodilator, an anti-inflammatoryagent, a leukotriene antagonist, and an IgE blocker. In further oralternative embodiments, the compound of Formula (A) or Formula (B) isadministered prior to the second substance. In further or alternativeembodiments, the compound of Formula (A) or Formula (B) is administeredprior to the second substance. In further or alternative embodiments,the compound of Formula (A) or Formula (B) is administered with thesecond substance. In further or alternative embodiments, the compound ofFormula (A) or Formula (B) is administered after the second substance.In further or alternative embodiments, the compound of Formula (A) orFormula (B) and the second substance are administered in the samepharmaceutical composition.

In further or alternative embodiments, the Ar is a group comprising asubstituted, optionally further substituted six-membered aromaticheterocycle. In further or alternative embodiments, said optionalsubstituents are selected from halogen, OH, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl. In further or alternative embodiments, the compound is thecompound of any of Formula (1) to Formula (54) in various embodimentsdescribed above.

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, the compound is selected from thegroup consisting of: tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzylamino)acetate,2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid, tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,tert-butyl2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,tert-butyl2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenylacetate, ethyl2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,methyl4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoicacid, methyl2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,tert-butyl3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylicacid,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoicacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylicacid, ethyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)aceticacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylicacid, 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylmorpholine-4-carboxylate,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate,4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)aceticacid, methyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoicacid,(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylicacid,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylicacid,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,methyl4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide,and(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(B) is selected from the group consisting of

—CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(E) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In another aspect are methods of using compounds having the structure ofFormula (A) or Formula (B) in the manufacture of a medicament fortreating a disease or condition in an animal in which c-kit receptoractivity contributes to the pathology and/or symptomology of the diseaseor condition:

wherein;

-   -   Q₁ is H, halogen, a group comprising a non-aromatic tertiary        amine, a group comprising a non-aromatic secondary amine, or is        an optionally substituted moiety selected from the group        consisting of: -L-alkyl, -L-cycloalkyl, -L-heteroalkyl,        -L-haloalkyl, -L-aryl, -L-heterocycloalkyl, and -L-heteroaryl;        wherein L is selected from a bond, —O—, —NH—, —S—, —C(O)—,        —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″YC(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y is optionally substituted        arylene or heteroarylene;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y′ is optionally        substituted arylene or heteroarylene;    -   Q₂ is selected from the group consisting of H, halogen, and a        group comprising an optionally substituted moiety selected from        -L₆-alkyl, -L₆-cycloalkyl, -L₆-heteroalkyl, -L₆-haloalkyl,        -L₆-aromatic carbocycle, -L₆-heterocycloalkyl, and -L₆-aromatic        heterocycle; wherein L₆ is selected from a bond, —O—, —NH—, —S—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,        —C(O)—NR″Y″C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y″ is        optionally substituted arylene or heteroarylene;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   any two R1 groups together may form an optionally substituted 5        to 8-membered heterocyclic, cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl, wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In a further or alternative embodiment of this aspect, compounds ofFormula (A) or Formula (B) are compounds having the structure of Formula(1) or Formula (46):

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   or any two adjacent R1 groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring;        or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, pharmaceutically active metabolite,        pharmaceutically acceptable prodrug, or pharmaceutically        acceptable solvate thereof.

In further or alternative embodiments, the Ar is a group comprising asubstituted, optionally further substituted six-membered aromaticheterocycle. In further or alternative embodiments, said optionalsubstituents are selected from halogen, OH, halogen, C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl. In further or alternative embodiments, the compound is thecompound of any of Formula (1) to Formula (54) in various embodimentsdescribed above.

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Q is selected from the groupconsisting of

In further or alternative embodiments, Ar is selected from the groupconsisting of

In further or alternative embodiments, the compound is selected from thegroup consisting of: tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzylamino)acetate,tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzylamino)acetate,2,2′-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethylazanediyl)diethanol,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid, tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate,N-(4-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenoxy)ethyl)piperidine-4-carboxylicacid,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,tert-butyl2-(4-(2-(4-(2-morpholinoethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,tert-butyl2-(4-(2-(4-(2-(4-carbamoylpiperidin-1-yl)ethoxy)phenylamino)pyrimidin-5-yl)benzamido)acetate,4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)phenylacetate, ethyl2-(2-(diethylamino)ethoxy)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,5-(4-methoxyphenyl)-N-(4-(2-(methyl(pyridin-2-yl)amino)ethoxy)phenyl)pyrimidin-2-amine,methyl4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)benzoate,N-(4-(2-(diethylamino)ethoxy)phenyl)-5-(3-fluoro-4-methoxyphenyl)pyrimidin-2-amine,2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoicacid, methyl2-(2-(diethylamino)ethoxy)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoate,N-(3-(2-(diethylamino)ethoxy)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-4-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxamide,tert-butyl3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propanoate,5-(4-methoxyphenyl)-N-(4-(piperazin-1-ylmethyl)phenyl)pyrimidin-2-amine,1-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)ethanone,(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)(tetrahydrofuran-2-yl)methanone,1-(3-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)propyl)pyrrolidin-2-one,(S)-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-2-yl)methanol,(R)-N-(4-((2-(methoxymethyl)pyrrolidin-1-yl)methyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidin-3-ol,methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzylamino)cyclopentanecarboxylate,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)-2-methylpiperazine-1-carboxylicacid,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazin-1-yl)propanoicacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidine-3-carboxylicacid, ethyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)acetate,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperidin-4-yl)aceticacid,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)pyrrolidine-3-carboxylicacid, 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylmorpholine-4-carboxylate,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,3-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl)piperazine-1-carboxylate,4-(5-(4-((2-tert-butoxy-2-oxoethylamino)methyl)phenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,2-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone,N1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1,4-dicarboxamide,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate,4-hydroxy-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperidine-1-carboxamide,N-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxamide,furan-2-yl(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)methanone,5-(4-methoxyphenyl)-N-(4-(2-(piperazin-1-yl)ethyl)phenyl)pyrimidin-2-amine,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-N,4-dimethylpiperazine-1-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid, methyl4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazine-1-carboxylate,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)aceticacid, methyl2-(1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidin-4-yl)acetate,(3-(hydroxymethyl)piperidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(3-hydroxypyrrolidin-1-yl)(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-4-carboxamide,3-(4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperazin-1-yl)propanoicacid,(S)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)pyrrolidine-2-carboxylicacid,4-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethylamino)cyclohexanecarboxylicacid,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(3-(2-oxopyrrolidin-1-yl)propyl)benzamide,1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-carbamoylphenyl)-4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzamide,1,4′-bipiperidin-1′-yl(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(2-(pyridin-2-yl)ethyl)benzamide,4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(4-(furan-2-carbonyl)piperazin-1-yl)(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)-N-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzamide,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(1-methylpiperidin-4-yl)piperazin-1-yl)methanone,1-(4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperazin-1-yl)ethanone,(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(4-(pyrrolidin-1-yl)piperidin-1-yl)methanone,1,4′-bipiperidin-1′-yl(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)methanone,1-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzoyl)piperidine-3-carboxamide,N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide,methyl4-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenylcarbamoyl)piperazine-1-carboxylate,(R)-1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-3-carboxylicacid,(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone,4-acetyl-N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)piperazine-1-carboxamide,and(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)(piperazin-1-yl)methanone.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(A) is selected from —NH₂, —NEt₂, and —NH(CH₂)_(n)OH; and n is1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(B) is selected from the group consisting of

—CH₂OH, —CH₂CH₂OH, and —CH₂CH₂CH₂OH.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(C) is at 2, 3, or 4 position of the piperidine ring; andR_(C) is selected from the group consisting of —C(O)NHEt, —C(O)NEt₂,c-butyl, c-pentyl, —C(O)NH-thiazole, oxazole, thiazole, —S(O)₂NH₂,—S(O)₂NHEt, and —S(O)₂NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

each R_(D) is independently selected from —(CH₂)_(k)OH or—(CH₂)_(k)CO₂H; and k is 1 to 6.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is

wherein R_(E) is at 2, 3, or 4 position of the piperidine ring; andR_(E) is selected from the group consisting of —C(O)NH₂, —C(O)NHEt, and—C(O)NEt₂.

In further or alternative embodiments, Q of the compound having thestructure of Formula (1) is selected from the group consisting of

wherein R_(F) is thiazole, pyrazole, or isoxazole.

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, Q of the compound having thestructure of Formula (46) is selected from the group consisting of

In further or alternative embodiments, the disease is a neoplasticdisease. In further or alternative embodiments, the disease is aneoplastic diseases selected from the group consisting of mastocytosis,canine mastocytoma, human gastrointestinal stromal tumor, small celllung cancer, non-small cell lung cancer, acute myelocytic leukemia,acute lymphocytic leukemia, myelodysplastic syndrome, chronicmyelogenous leukemia, colorectal carcinomas, gastric carcinomas,gastrointestinal stromal tumors, testicular cancers, glioblastomas, andastrocytomas.

In further or alternative embodiments, the disease is an allergydisease. In further or alternative embodiments, the disease is anallergic disease selected from the group consisting of asthma, allergicrhinitis, allergic sinusitis, anaphylactic syndrome, urticaria,angioedema, atopic dermatitis, allergic contact dermatitis, erythemanodosum, erythema multiforme, cutaneous necrotizing venulitis and insectbite skin inflammation and blood sucking parasitic infestation.

In further or alternative embodiments, the disease is an inflammatorydisease. In further or alternative embodiments, the disease is aninflammatory diseases selected from the group consisting of rheumatoidarthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, goutyarthritis and other arthritic conditions.

In further or alternative embodiments, the disease is an autoimmunedisease. In further or alternative embodiments, the disease is anautoimmune disease selected from the group consisting of multiplesclerosis, psoriasis, intestine inflammatory disease, ulcerativecolitis, Crohn's disease, rheumatoid arthritis and polyarthritis, localand systemic scleroderma, systemic lupus erythematosus, discoid lupuserythematosus, cutaneous lupus, dermatomyositis, polymyositis, Sjogren'ssyndrome, nodular panarteritis, autoimmune enteropathy, andproliferative glomerulonephritis.

In further or alternative embodiments, the disease is agraft-versus-host disease. In further or alternative embodiments, thedisease is organ transplantation graft rejection. In further oralternative embodiments, the organ transplantation is kidneytransplantation, pancreas transplantation, liver transplantation, hearttransplantation, lung transplantation, or bone marrow transplantation.

In further or alternative embodiments, the disease is a metabolicsyndrome. In further or alternative embodiments, the disease is ametabolic syndrome selected from type I diabetes, type II diabetes, orobesity.

In further or alternative embodiments, the condition is a CNS relateddisorder. In further or alternative embodiments, the disease is a CNSrelated disorders selected from the group consisting of depression,dysthymic disorder, cyclothymic disorder, bipolar depression, severe or“melancholic” depression, atypical depression, refractory depression,seasonal depression, anorexia, bulimia, premenstrual syndrome andpost-menopause syndrome, as mental slowing and loss of concentration,pessimistic worry, agitation, self-deprecation and decreased libido, asanxiety disorders including anxiety associated with hyperventilation andcardiac arrhythmias, phobic disorders, obsessive-compulsive disorder,posttraumatic stress disorder, acute stress disorder, and generalizedanxiety disorder, as psychiatric disorders such as panic attacks,including psychosis, delusional disorders, conversion disorders,phobias, mania, delirium, dissociative episodes including dissociativeamnesia, dissociative fugue and dissociative suicidal behavior,self-neglect, violent or aggressive behavior, trauma, borderlinepersonality, and acute psychosis as schizophrenia including paranoidschizophrenia, disorganized schizophrenia, catatonic schizophrenia, andundifferentiated schizophrenia.

In further or alternative embodiments, the disease is aneurodegenerative disease. In further or alternative embodiments, thedisease is a neurodegenerative disease selected from the groupconsisting of Alzheimer's disease, Parkinson's disease, Huntington'sdisease, the prion diseases, Motor Neuron Disease (MND), and AmyotrophicLateral Sclerosis (ALS).

In further or alternative embodiments, the condition is pain. In furtheror alternative embodiments, the type of pain is selected from the groupconsisting of acute pain, postoperative pain, chronic pain, nociceptivepain, cancer pain, neuropathic pain, and psychogenic pain syndromes.

In further or alternative embodiments, the condition is a substance usedisorder. In further or alternative embodiments, the condition is asubstance use disorder selected from the group consisting of drugaddiction, drug abuse, drug habituation, drug dependence, withdrawalsyndrome and overdose.

In further or alternative embodiments, the disease is a prion disease.

In further or alternative embodiments, the disease is cancer. In furtheror alternative embodiments, the disease is cancer selected from thegroup consisting of melanoma, gastrointestinal stromal tumor (GIST),small cell lung cancer, and other solid tumors.

In further or alternative embodiments, the disease is heart disease.

In further or alternative embodiments, the disease is a fibroticdisease. In further or alternative embodiments, the disease is afibrotic disease selected from the group consisting of hepatitis C(HCV),liver fibrosis, nonalcoholic steatohepatitis (NASH), cirrhosis in liver,pulmonary fibrosis, and bone marrow fibrosis.

In further or alternative embodiments, the disease is idiopathicpulmonary arterial hypertension (IPAH).

In further or alternative embodiments, the disease is primary pulmonaryhypertension (PPH).

In another aspect are methods for making the compounds having thestructure of Formula (1) comprising admixing a compound of structure:

with a compound having the structure:

under suitable reaction conditions to yield a compound having thestructure of Formula (C):

and further admixing the compound having the structure of Formula (C)with a compound of structure: ArB(OH)₂, under suitable reactionconditions.

In another aspect are methods for making the compounds having thestructure of Formula (1) comprising admixing a compound of structure:

with a compound having the structure:

under suitable reaction conditions to yield a compound having thestructure of Formula (C):

and further admixing the compound having the structure of Formula (C)with a compound of structure: ArB(OH)₂, under suitable reactionconditions.

Other objects, features and advantages of the methods and compositionsdescribed herein will become apparent from the following detaileddescription. It should be understood, however, that the detaileddescription and the specific examples, while indicating specificembodiments, are given by way of illustration only, since variouschanges and modifications within the spirit and scope of the inventionwill become apparent to those skilled in the art from this detaileddescription.

These and other aspects of the present invention will become evidentupon reference to the following detailed description. In addition, allpatents and other references cited herein which describe in more detailcertain procedures or compositions, and are incorporated by reference intheir entirety.

DETAILED DESCRIPTION OF THE INVENTION Certain Chemical Terminology

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg “ADVANCED ORGANIC CHEMISTRY 4^(TH) ED.” Vols. A(2000) and B (2001), Plenum Press, New York. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

The term “alkenyl group,” as used herein, refers to a hydrocarbon chainhaving one or more double bonds therein. The double bond of an alkenylgroup can be unconjugated or conjugated to another unsaturated group.Suitable alkenyl groups include, but are not limited to, (C₂-C₈)alkenylgroups, such as vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl,pentadienyl, hexadienyl, 2-ethylhexenyl, 2-propyl-2-butenyl,4-(2-methyl-3-butene)-pentenyl. The alkenyl moiety may be branched,straight chain, or cyclic (in which case, it would also be known as a“cycloalkenyl” group), and can be unsubstituted or substituted.

The term “alkoxy” as used herein, includes —O-(alkyl), where alkyl is asdefined herein. By way of example only, C₁₋₆ alkoxy includes, but is notlimited to, methoxy, ethoxy, and the like. An alkoxy group can beunsubstituted or substituted.

The term “alkyl,” as used herein, refers to a hydrocarbon group havingfrom 1 to 10 carbon atoms and can include straight, branched, cyclic,saturated and/or unsaturated features. Whenever it appears herein, anumerical range such as “1 to 10” refers to each integer in the givenrange; e.g., “1 to 10 carbon atoms” or “C₁₋₁₀” or “(C₁-C₁₀)” means thatthe alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbonatoms, etc., up to and including 10 carbon atoms, although the presentdefinition also covers the occurrence of the term “alkyl” where nonumerical range is designated. The alkyl moiety may be a “saturatedalkyl” group, which means that it does not contain any alkene or alkynemoieties. Representative saturated alkyl groups include, but are notlimited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl,2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, sec-butyl, t-butyl, n-pentyl,isopentyl, neopentyl, and n-hexyl, and longer alkyl groups, such asheptyl, and octyl. The alkyl moiety may also be an “unsaturated alkyl”moiety, which means that it contains at least one alkene or alkynemoiety. An “alkene” moiety refers to a group consisting of at least twocarbon atoms and at least one carbon-carbon double bond, and an “alkyne”moiety refers to a group consisting of at least two carbon atoms and atleast one carbon-carbon triple bond. Representative unsaturated alkylgroups include, but are not limited to, ethenyl, propenyl, butenyl andthe like. An alkyl group can be unsubstituted or substituted.Substituted alkyl groups include, but are not limited to,halogen-substituted alkyl groups, such as, by way of example only,trifluoromethyl, pentafluoroethyl, and the like.

The term “alkylamine,” as used herein, refers to the —N(alkyl)_(x)H_(y)group, where x and y are selected from the group x=1, y=1 and x=2, y=0.When x=2, the alkyl groups, taken together, can optionally form a cyclicring system and further when x=2, the alkyl groups can be the same ordifferent. An alkylamine group can be unsubstituted or substituted.

The term “alkynyl” group, as used herein, refers to a hydrocarbon chainhaving one or more triple bonds therein. The triple bond of an alkynylgroup can be unconjugated or conjugated to another unsaturated group.Suitable alkynyl groups include, but are not limited to, (C₂-C₆)alkynylgroups, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl,methylpropynyl, 4-methyl-1-butynyl, 4-propyl-2-pentynyl, and4-butyl-2-hexynyl. The alkynyl moiety may be branched or straight chain,and can be unsubstituted or substituted.

The term “amide,” as used herein, refers to a chemical moiety withformula —C(O)NHR or —NHC(O)R, where R is selected from the groupconsisting of alkyl, cycloalkyl, aryl, and heterocyclic (bonded througha ring carbon). Amides can be formed from any amine or carboxyl sidechain on the compounds described herein. The procedures and specificgroups to make such amides are known to those of skill in the art andcan readily be found in reference sources such as Greene and Wuts,Protective Groups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons,New York, N.Y., 1999, which is incorporated herein by reference in itsentirety. An amide group can be unsubstituted or substituted.

The term “aromatic” or “aryl,” as used herein, refers to a closed ringstructure which has at least one ring having a conjugated pi electronsystem and includes both carbocyclic aryl and heterocyclic aryl (or“heteroaryl” or “heteroaromatic”) groups. The carbocyclic orheterocyclic aromatic group may contain from 5 to 20 ring atoms. Theterm includes monocyclic or fused-ring polycyclic (i.e., rings whichshare adjacent pairs of carbon atoms) groups. An aromatic group can beunsubstituted or substituted.

The term “aryloxy,” as used herein, includes —O-aryl group, wherein arylis as defined herein. An aryloxy group can be unsubstituted orsubstituted.

The term “bond” or “single bond,” as used herein, refers to a covalentbond between two atoms, either of which may be part of a larger moiety.

The terms “carbocyclic” or “cycloalkyl,” as used herein, refer to acompound which contains one or more covalently closed ring structures,and that the atoms forming the backbone of the ring are all carbonatoms. Such a group may have from 3 to 20 ring carbon atoms and besaturated, partially unsaturated, or fully unsaturated monocyclic, fusedbicyclic, spirocyclic, bridged polycyclic or polycyclic ring comprisingcarbon and hydrogen atoms. Carbocyclic alkyl groups include, but are notlimited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. A carbocyclic aromatic group includes, butis not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl,azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties suchas, by way of example only, dibenzosuberenone, and dibenzosuberone. Acarbocyclic group can be unsubstituted or substituted.

The term “ester,” as used herein, refers to a chemical moiety withformula —COOR, where R is selected from the group consisting of alkyl,cycloalkyl, aryl, and heterocyclic (bonded through a ring carbon). Anyhydroxy or carboxyl side chain on the compounds described herein can beesterified. The procedures and specific groups to make such esters areknown to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis,3^(rd) Ed., John Wiley & Sons, New York, N.Y., 1999, which isincorporated herein by reference in its entirety. An ester group can beunsubstituted or substituted.

The terms “heteroalkyl” “heteroalkenyl” and “heteroalkynyl,” as usedherein, include optionally substituted alkyl, alkenyl and alkynylmoieties and which have one or more skeletal chain atoms selected froman atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus orcombinations thereof. A “heteroalkyl” “heteroalkenyl” and“heteroalkynyl” group can be unsubstituted or substituted.

The terms “heteroaryl” or, alternatively, “heteroaromatic,” as usedherein, refers to an aryl group that includes one or more ringheteroatoms selected from nitrogen, oxygen, sulfur. By way of example,an N-containing “heteroaromatic” or “heteroaryl” moiety refers to anaromatic group in which at least one of the skeletal atoms of the ringis a nitrogen atom. A polycyclic heteroaryl group may be fused ornon-fused. A heteroaryl group can be unsubstituted or substituted.

The term “heterocyclic,” as used herein, refers to ring structures inwhich the ring backbone contains at least one atom selected fromnitrogen, oxygen, and sulfur. Examples of heterocyclic aromatic groupsinclude, but are not limited to, acridinyl, benzo[1,3]dioxole,benzimidazolyl, benzindazolyl, benzoisooxazolyl, benzokisazolyl,benzofuranyl, benzofurazanyl, benzopyranyl, benzothiazolyl,benzo[b]thienyl, benzothiophenyl, benzothiopyranyl, benzotriazolyl,benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, furazanyl,furopyridinyl, furyl, imidazolyl, indazolyl, indolyl, indolidinyl,indolizinyl, isobenzofuranyl, isoindolyl, isoxazolyl, isoquinolinyl,isothiazolyl, naphthylidinyl, naphthyridinyl, oxadiazolyl, oxazolyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiynyl, thianthrenyl,phenathridinyl, phenathrolinyl, phthalazinyl, pteridinyl, purinyl,puteridinyl, pyrazyl, pyrazolyl, pyridyl, pyridinyl, pyridazinyl,pyrazinyl, pyrimidinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolinyl,quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl,(1,2,3,)- and (1,2,4)-triazolyl and the like. In addition, aheterocyclic group can be unsubstituted or substituted. Examples ofnon-aromatic heterocyclic groups include, but are not limited to, areazepinyl, azepan-2-onyl, azetidinyl, diazepinyl, dihydrofuranyl,dihydropyranyl, dihydrothienyl, dioxanyl, dioxolanyl,1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, dithianyl, dithiolanyl,homopiperidinyl, imidazolinyl, imidazolidinyl, indolinyl, indolyl,morpholinyl, oxazepinyl, oxepanyl, oxetanyl, oxylanyl, piperidino,piperidyl, piperidinonyl, piperazinyl, pyranyl, pyrazolinyl,pyrazolidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolinyl, quinolizinyl,thietanyl, tetrahydrofuranyl, tetrahydroquinolyl, tetrahydrothienyl,tetrahydrothiopyranyl, tetrahydropyridinyl, tetrahydropyranyl,thiazepinyl, thiepanyl, thiomorpholinyl, thioranyl, thioxanyl and thelike. The heterocyclic group may be fused or non-fused. The termsreferring to the groups also encompass all possible tautomers.

The term “halogen,” as used herein, means fluoro, chloro, bromo or iodo.Preferred halogen groups are fluoro, chloro and bromo.

The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl” and “haloalkoxy”include alkyl, alkenyl, alkynyl and alkoxy structures that aresubstituted with one or more halogen groups or with combinationsthereof.

The term “membered ring,” as used herein, can embrace any cyclicstructure. The term “membered” is meant to denote the number of skeletalatoms that constitute the ring. Thus, for example, cyclohexyl, pyridine,pyran and thiopyran are 6-membered rings and cyclopentyl, pyrrole,furan, and thiophene are 5-membered rings.

The term “moiety,” as used herein, refers to a specific segment orfunctional group of a molecule. Chemical moieties are often recognizedchemical entities embedded in or appended to a molecule.

The term “protecting group,” as used herein, refers to a chemical moietywhich blocks some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved.

The term “reactant,” as used herein, refers to a nucleophile orelectrophile used to create covalent linkages.

The term “sulfonyl” refers to the presence of a sulfur atom, which isoptionally linked to another moiety such as an alkyl group, an arylgroup, or a heterocyclic group. Aryl or alkyl sulfonyl moieties have theformula —SO₂R′, wherein R′ is alkyl or aryl as defined herein, andinclude, but are not limited to, methylsulfonyl, ethylsulfonyl andphenylsulfonyl groups. A sulfonyl group can be unsubstituted orsubstituted. A phenylsulfonyl is optionally substituted with 1 to 3substituents independently selected from halogen, alkyl, and alkoxy.

Unless otherwise indicated, when a substituent is deemed to be“optionally substituted,” it is meant that the substituent is a groupthat may be substituted with one or more group(s) individually andindependently selected from, for example, alkenyl, alkyl, alkoxy,alkylamine, alkylthio, alkynyl, amide, amino, including mono- anddi-substituted amino groups, aryl, aryloxy, arylthio, carbonyl,carbocyclic, cyano, cycloalkyl, halogen, heteroalkyl, heteroalkenyl,heteroalkynyl, heteroaryl, heterocyclic, hydroxy, isocyanato,isothiocyanato, mercapto, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl,N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido,C-carboxy, O-carboxy, perhaloalkyl, perfluoroalkyl, silyl, sulfonyl,thiocarbonyl, thiocyanato, trihalomethanesulfonyl, and the protectedcompounds thereof. The protecting groups that may form the protectedcompounds of the above substituents are known to those of skill in theart and may be found in references such as Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3^(rd) Ed., John Wiley & Sons, New York,N.Y., 1999, and Kocienski, Protective Groups, Thieme Verlag, New York,N.Y., 1994, which are incorporated herein by reference in theirentirety.

Certain Pharmaceutical Terminology

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

The term “agonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme activator or a hormone modulator whichenhances the activity of another molecule or the activity of a receptorsite.

The term “antagonist,” as used herein, refers to a molecule such as acompound, a drug, an enzyme inhibitor, or a hormone modulator, whichdiminishes, or prevents the action of another molecule or the activityof a receptor site.

The term “carrier,” as used herein, refers to relatively nontoxicchemical compounds or agents that facilitate the incorporation of acompound into cells or tissues.

The terms “co-administration” or the like, as used herein, are meant toencompass administration of the selected therapeutic agents to a singlepatient, and are intended to include treatment regimens in which theagents are administered by the same or different route of administrationor at the same or different time.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of an agent or a compoundbeing administered which will relieve to some extent one or more of thesymptoms of the disease or condition being treated. The result can bereduction and/or alleviation of the signs, symptoms, or causes of adisease, or any other desired alteration of a biological system. Forexample, an “effective amount” for therapeutic uses is the amount of thecomposition comprising a compound as disclosed herein required toprovide a clinically significant decrease in a disease. An appropriate“effective” amount in any individual case may be determined usingtechniques, such as a dose escalation study.

The terms “enhance” or “enhancing,” as used herein, means to increase orprolong either in potency or duration a desired effect. Thus, in regardto enhancing the effect of therapeutic agents, the term “enhancing”refers to the ability to increase or prolong, either in potency orduration, the effect of other therapeutic agents on a system. An“enhancing-effective amount,” as used herein, refers to an amountadequate to enhance the effect of another therapeutic agent in a desiredsystem.

The terms “kit” and “article of manufacture” are used as synonyms.

The term “metabolite,” as used herein, refers to a derivative of acompound which is formed when the compound is metabolized.

The term “active metabolite,” as used herein, refers to a biologicallyactive derivative of a compound that is formed when the compound ismetabolized.

The term “metabolized,” as used herein, refers to the sum of theprocesses (including, but not limited to, hydrolysis reactions andreactions catalyzed by enzymes) by which a particular substance ischanged by an organism. Thus, enzymes may produce specific structuralalterations to a compound. For example, cytochrome P450 catalyzes avariety of oxidative and reductive reactions while uridine diphosphateglucuronyltransferases catalyze the transfer of an activatedglucuronic-acid molecule to aromatic alcohols, aliphatic alcohols,carboxylic acids, amines and free sulphydryl groups. Further informationon metabolism may be obtained from The Pharmacological Basis ofTherapeutics, 9th Edition, McGraw-Hill (1996).

The term “modulate,” as used herein, means to interact with a targeteither directly or indirectly so as to alter the activity of the target,including, by way of example only, to enhance the activity of thetarget, to inhibit the activity of the target, to limit the activity ofthe target, or to extend the activity of the target.

The term “modulator,” as used herein, refers to a molecule thatinteracts with a target either directly or indirectly. The interactionsinclude, but are not limited to, the interactions of an agonist and anantagonist.

By “pharmaceutically acceptable,” as used herein, refers a material,such as a carrier or diluent, which does not abrogate the biologicalactivity or properties of the compound, and is relatively nontoxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which if is contained.

The term “pharmaceutically acceptable salf” of a compound, as usedherein, refers to a salt that is pharmaceutically acceptable.

The term “pharmaceutical combination” as used herein, means a productthat results from the mixing or combining of more than one activeingredient and includes both fixed and non-fixed combinations of theactive ingredients. The term “fixed combination” means that the activeingredients, e.g. a compound of Formula (A) or Formula (B) and aco-agent, are both administered to a patient simultaneously in the formof a single entity or dosage. The term “non-fixed combination” meansthat the active ingredients, e.g. a compound of Formula (A) or Formula(B) and a co-agent, are administered to a patient as separate entitieseither simultaneously, concurrently or sequentially with no specificintervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter alsoapplies to cocktail therapy, e.g. the administration of three or moreactive ingredients.

The term “pharmaceutical composition,” as used herein, refers to amixture of an active compound with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients.

A “prodrug,” as used herein, refers to a drug or compound in whichmetabolic processes within the body converts the drug or compound into apharmacological active form.

The term “subject” or “patient” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the methods andcompositions provided herein, the mammal is a human.

The terms “treat,” “treating” or “treatment,” as used herein, includealleviating, abating or ameliorating a disease or condition symptoms,preventing additional symptoms, ameliorating or preventing theunderlying metabolic causes of symptoms, inhibiting the disease orcondition, e.g., arresting the development of the disease or condition,relieving the disease or condition, causing regression of the disease orcondition, relieving a condition caused by the disease or condition, orstopping the symptoms of the disease or condition.

Illustrative Biological Activity

Presented herein are 5-substituted-2-aminopyrimidine compounds whichselectively modulate, regulate, and/or inhibit signal transductionmediated by certain native and/or mutant tyrosine kinases implicated ina variety of human and animal diseases such as cell proliferative,metabolic, allergic, and degenerative disorders. By way of example only,these compounds are potent and selective c-kit inhibitors.

c-Kit Receptor

Mast cells are tissue elements derived from a particular subset ofhematopoietic stem cells that express CD34, c-kit and CD13 antigens.Mast cells are characterized by their heterogeneity, not only regardingtissue location and structure but also at the functional andhistochemical levels. Immature mast cell progenitors circulate in thebloodstream and differentiate into various tissues. Thesedifferentiation and proliferation processes are under the influence ofcytokines, one of utmost importance being Stem Cell Factor (SCF), alsotermed Kit ligand, Steel factor or Mast Cell Growth Factor. The StemCell Factor receptor is encoded by the protooncogene, c-kit, which isexpressed in hematopoietic progenitor cells, mast cells, germ cells,interstitial cells of Cajal (ICC), and some human tumors, and is alsoexpressed by non hematopoietic cells.

Tyrosine kinases are receptor type or non-receptor type proteins, whichtransfer the terminal phosphate of ATP to tyrosine residues of proteinsthereby activating or inactivating signal transduction pathways. TheStem Cell Factor receptor, c-kit, is a Type III transmembrane receptorprotein tyrosine kinase which initiates cell growth and proliferationsignal transduction cascades in response to SCF binding. Ligation ofc-kit receptor by SCF induces its dimerization followed by itstransphorilation, leading to the recruitement and activation of variousintracytoplasmic substrates. These activated substrates induce multipleintracellular signaling pathways responsible for cell proliferation andactivation. These proteins are known to be involved in many cellularmechanisms, which in case of disruption, lead to disorders such asabnormal cell proliferation and migration, as well as inflammation.

The activity of the c-kit receptor protein tyrosine kinase is regulatedin normal cells, and the normal functional activity of the c-kit geneproduct is essential for maintenance of normal hematopoeisis,melanogenesis, genetogensis, and growth and differentiation of mastcells. In addition to its importance in normal cellular physiologicactivities, c-kit plays a role in the biological aspects of certainhuman cancers, and unregulated c-kit kinase activity is implicated inthe pathogenesis of human cancers, and in certain tumors types.Proliferation of tumor cell growth mediated by c-kit can occur by aspecific mutation of the c-kit polypeptide that results in ligandindependent activation or by autocrine stimulation of the receptor. Inthe former case, mutations that cause constitutive activation of c-kitkinase activity in the absence of SCF binding are implicated inmalignant human cancers, including germ cell tumors, mast cell tumors,gastrointestinal stromal tumors, small-cell lung cancer, melanoma,breast cancer, acute myelogenous leukemia, neuroblastoma andmastocytosis.

Mast cells present in tissues of patients are implicated in orcontribute to the genesis of diseases such as autoimmune diseases(multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases(IBD)) allergic diseases (allergic sinusitis, allergic rhinitis andasthma), tumor angiogenesis, inflammatory diseases, and interstitialcystitis. In these diseases, mast cells participate in the destructionof tissues by releasing a cocktail of different proteases and mediatorssuch as histamine, neutral proteases, lipid-derived mediators(prostaglandins, thromboxanes and leucotrienes), and various cytokines(IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNF-α, GM-CSF, MIP-LA,MIP-1b, MIP-2 and IFN-γ).

Human are more and more afflicted in modern societies with allergicdisorders such as allergic sinusitis, allergic rhinitis and asthma. Forexample, in the USA alone, it is estimated that more than 87 millionpeople are coping with some form of allergic diseases. The financialburden of the treatments rises to a total of several billion dollars andis due to the recurrence of these diseases. Among these allergicdiseases, we can cite allergic rhinitis, allergic sinusitis,anaphylactic syndrome, urticaria, angioedema, atopic dermatitis,allergic contact dermatitis, erythema nodosum, erythema multiforme,cutaneous necrotizing venulitis and insect bite skin inflammation, butbronchial asthma is the most prevalent and recurrent disease severelyafflicting the human population.

Asthma is characterized by airflow obstruction, bronchialhyperresponsiveness and airway inflammation. Airway inflammation is themajor factor in the development and perpetuation of asthma. In allergicasthma, which is the most frequent, especially in children, and betterstudied form of the disease, allergens are thought to initiate theinflammatory process by inducing a T-lymphocyte mediated response (TH2)that results in the production of allergen-specific IgE. IgE bind to itshigh-affinity receptor FCERI on pulmonary mast cells triggering a type I(IgE-mediated) immediate allergic response.

Mast cell activation induces diverse effector responses, such assecretion of allergic mediators, proteases, chemokines such as MCP-1 andRANTES, leukotrienes, prostaglandins, neurotrophins, induction ofcytokine gene transcription (IL-4, IL-5, IL-6, IL-13, TNFA and GM-CSF).These mediators contribute to creating the asthmatic phenotype by theireffects on endothelial cells, smooth muscle cells and fibroblasts and onextracellular matrix, and by recruiting other inflammatory cells.

Different treatments are available to alleviate the symptoms associatedwith allergic diseases. For instance, treatments for severe allergicdiseases such as asthma, include combination of histamine H₁-receptorantagonists with antagonists of leukotriene receptors or 5-lipoxygenaseinhibitors . However, anti-histamine compounds have been found to beless effective and do not provide a solution to the recurrence ofasthma, and the latter treatment only reduces inflammation symptomsassociated with allergic diseases and cannot be considered as a cure onthe long run. In response to this problem, interleukin-2 (IL-2) has beenused to suppress allergic disorders, but the induction of death byapoptosis of a subpopulation of T lymphocytes has many side effectslimiting such therapy to the most severe forms of allergic diseases.

Mast cells may play a role in asthma as suggested by the humanizedanti-IgE monoclonal antibody treatment. The rationale of anti-IgEtherapy is to specifically target IgE with the result of inactivatingfree anti-IgE and halting further IgE production. In addition, since IgElevels are a major regulator of the level of expression of IgE receptorFceRI, one aim of this therapy is to decrease FceRI expression on mastcells and basophils, and, as a consequence, to decrease the capacity ofthese cells to be activated. The capacity of the anti-IgE therapy todecrease FceRI expression has been demonstrated on basophils. Thedecrease in FceRI expression on basophils is associated with a decreasein the capacity of basophils to secrete mediators upon activation. Eventhough the effect of the anti-IgE therapy on pilmonary mast cells hasnot been studied because these cells are difficult to harvest. Thesetrials have shown that the anti-IgE therapy is capable of improving someof the parameters of asthma, for example corticosteroid usage.Nevertheless, antibody based therapy is not suitable to repeatedtreatment of the most recurrent forms of allergic diseases. In addition,compositions comprising tryptase inhibitors for treating mast-cellmediated conditions are may be used, but decreasing the activity of freetryptase released by activated mast cells is not sufficient to blockchain reactions caused by the others mast cells released factors.Therefore, there is a need for alternative treatments of allergicdiseases and/or conditions which would be more effective on the longterm and would be well tolerated, especially in respect to repeatedadministration.

Non-insulin-dependent diabetes mellitus (NLDDM), also known as type IIdiabetes, is defined as a chronic disease appearing when insulin isinefficient in promoting glucose uptake by cells, resulting in increasedlevels of glucose in the blood. This disease affects about 100 millionpeople world-wide, 75% of which are obese at the time of diagnosis.

Diminution in the ability of the cells to respond adequately to insulinis often referred as insulin resistance. Excessive weight and lack ofphysical activity are regarded as being responsible for inducing insulinresistance. Over many years, the failure of the glucose uptakeregulation leads to the development of Type II diabetes and the bloodglucose level needs to be regulated with medicinal products. Ultimately,unregulated blood glucose level is responsible for blood vessels, kidneyand eye damages, as well as cardiovascular diseases. This tissue damagescontribute to mortality in diabetics.

Hypoglycemic agents such as sulfonylureas work by triggering thepancreas to make more insulin, which lower blood glucose. The sideeffects of sulfonylureas include hypoglycemia, renal and hepaticdisease, gastrointestinal disturbances, increased cardiovascularmortality, dermatological reactions, drowsiness and headache. Biguanideslower blood glucose levels by reducing intestinal glucose absorption andhepatic glucose, but not by stimulating insulin secretion. The majorside effects of biguanidine are lactic acidosis and increasedcardiovascular mortality. Alpha-glucosidase inhibitors decrease theabsorption of carbohydrates from the digestive tract, thereby loweringthe after-meal glucose level, but gastrointestinal side effects andhypoglycemia are observed. Thiazolidinediones, such as rosiglitazone arePPARgamma agonists and increase the cell's sensitivity to insulin.However, they may be responsible for water retention, liver diseases,cardiovascular diseases, red blood cell abnormalities, and headache.

Because treatment of Type II diabetes requires long term administrationof compounds lowering blood glucose level, there is still a great needfor improved and safer methods. C-kit inhibitors may also be used in thetreatment of type II diabetes. Inhibition of c-kit activity reducescellular proliferation, depleting the mast cells responsible fordiseases and/or conditions, such as allergic diseases, therebysuggesting a role for use of inhibitors of c-kit in the treatment ofc-kit dependent diseases and/or conditions, such as diabetes. Describedherein are diarylamine compounds, pharmaceutical compositions andmedicaments, which include such diarylamine compounds or apharmaceutically acceptable salt or solvate thereof, that are potent andselective c-kit inhibitors and which selectively modulate, regulate,and/or inhibit signal transduction mediated by certain native and/ormutant tyrosine kinases implicated in a variety of human and animaldiseases such as, by way of example only, diabetes.

Neurons propagate a signal in the form of an action potential along itsaxon to other neurons or to effector cells. Many positive or negativesignals are exchanged between neurons and are integrated to producemeaningful firing patterns. The communication between two neurons isbased on the action of numerous neurotransmitters on specific receptorslocated at the synapses. A disruption in the regulation ofneurotransmission is responsible for neurologic and psychiatricdiseases. Furthermore, the activity of neurotransmitters on theirrespective receptor is normally time limited so that receptors canrespond repeatedly to the next waves of stimuli. In this regard,different mechanisms abolish the action of neurotransmitters, forinstance they can be pumped back into the presynaptic nerve terminals byactive processes (reuptake), they can be destroyed by enzymes, or theysimply diffuse into the surrounding area.

Changes in neurotransmitter synthesis, storage, release, or degradationor changes in the number and affinity of receptors can affectneurotransmission and cause clinical disorders. Among neurotransmitters,glutamate and aspartate are the major excitatory neurotransmitters,whereas aminobutyric acid (GABA) is the major inhibitoryneurotransmitter in the brain. The first theory about depressionconcerned the noradrenergic system (NS) (Shildkraut J. et al. 1965, AmJ. Psychiat. 12: 509-522). At that time, it was observed that tricycliccompounds (ADT) and monoamine-oxidase inhibitors modified the level ofnoradrenaline. Later on, in 1978, Sulser F. et al., Biochem Pharmacol.27: 257-261 showed that these antidepressants lead to a decrease in thenumber of post-synaptic (3-Adrenergis receptors. Therefore, it wasthought that depression was due to the deregulation of the noradrenergicpre-synaptic stimuli as well as the post-synaptic receptors (Siever L J.et AL. (1985), Am. J. Psychiat. 142, 1017-1031).

In 1986, Rasmussen et al., Brain Res. 385: 395-400 demonstrated thepresence of serotonin (5-hydroxytriptamin, 5-HT) receptors in NAneurones. Treatments with ADT were shown to provoke also adown-regulation of the 5-HT₂ receptors in Sugrue M. F. et al, 1981,Pharmacol. Ther. 13: 219-247. As a consequence, it appears that the NAand 5-HT systems play a crucial role in the regulation of mood andbehaviour. In the nineties, research has focused on the finding ofspecific serotonin re-uptake inhibitors (SSRI), such as fluoxetin,parxetin or sertralin (Pinder R. M. et al., 1993, Med. Res. Rev. 13:259-325). Serotonin (5-hydroxytryptamine, or 5-HT) levels are controlledby the uptake of tryptophan and intraneuronal monoamine oxidaseactivity. In the meantime, a decrease in the level of HVA, the maincatabolic of dopamin (DA), was observed in depressed patients (Kapur S.et al., 1992, Biol. Psychiat. 32: 1-17). GABA was also shown to beinvolved in the physiopathology of depression since (i) unpolar patientsdisplay decreased level of GABA, (ii) some antidepressants induce therelease of GABA in vivo and (iii) agonists of GABA receptors haveantidepressant effects (Lloyd K. G. et al., 1989, Prog.Neuro-Psycopharmacol. Biol. Psychiat. 13: 341-351).

More recently, it has been reported that other factors may be involvedin CNS disorders. For example, it has been observed from 30 to 70% ofpatients afflicted with melancholia have high level of plasmaticcortisol and escape to the test with dexamethasone described in CarollB. J. et al., 1981, Arch. Gen. Psychiat. 38: 15. In addition,cortocosteroids modify (i) the expression of serotoninergic receptorsand (ii) the activity of tryptophan hydroxylase, which is the key enzymein the synthesis of 5-HT (Biegon A., 1990, Ann. NY Acad. Sci. 600:427-431).

Regarding post-partum or post-menopause depression, repeatedadministration of oestrogene induces a down-regulation of dopaminergicD₂ receptors (Munemura M. et al., 1989, Endocrinology 124: 346-355 andRoy E. J. et al., 1990, Brain. Res. Bull. 25: 221-227).

Other neurotransmitters include the well known acetylcholine,norepinephrine which interacts with adrenergic receptors and which isregulated by tyrosine hydroxylase and monoamine oxidase, endorphinswhich are polypeptides that activate many central neurons and interactwith opioid receptors, enkephalins, dynorphins, histamine, vasopressin,vasoactive intestinal peptide, carnosine, bradykinin, cholecystokinin,bombesin, somatostatin, corticotropin releasing factor, neurotensin, andadenosine.

As mentioned above, any imbalance in these neurotransmifters or anyderegulation of associated receptors may lead to the development of CNSdisorders ranging from psychiatric diseases to migraine, pain, memoryloss and nerve cells degeneracy.

As of today, available treatments include selective serotonin reuptakeinhibitors (SSRIS) such as fluoxetine, sertraline, paroxetine, andfluvoxamine. Other compounds include nefaxodone which blocks the 5-HT₂receptor and inhibits reuptake of 5-HT and norepinephrine, trazodonewhich is a 5-HT₂ receptor blocker and a 1-noradrenergic blocker,mirtazapine which blocks 2-adrenergic autoreceptors as well as 5-HT₂,5-HT₃ and HI receptors, tricyclic compounds such as imipramine anddesipramine, tetracyclic compounds which increase the level of freenorepinephrine and of 5-HT, and monoamine oxidase inhibitors (MAOI)which inhibit the oxidative deamination of norepinephrine, dopamine, and5-HT. We can also cite lithium-antidepressants for treating bipolardisorder.

However, the above mentioned compounds display numerous side effectssuch as tachycardia, sedation and weight gain. In addition, thesecompounds are only effective in about 65% of depressed patients, whichimplies a large population afflicted with the so-called “refractorydepression”. In some cases, the life of patients is in jeopardy at theextent that hospitalization and electroconvulsive therapy is required,thus showing the seriousness of these diseases.

Schizophrenia is also a serious mental disorder affecting about 1% ofwestern countries population. Antipsychotic (neuroleptic) drugsavailable include chlorpromazine and haloperidol which show affinity forthe dopamine 2 receptor. But, adverse side effects such as sedation,dystonia, tremors and akathisia have been commonly observed and asignificant percentage of patients do not respond to the treatments.

Therefore, the problem is to find alternative solutions to provide arelief and a cure for the numerous patients afflicted with thesediseases. The activation of mast cells by different stimuli such asstress, trauma, infection as well as neurotransmitters, may participatein the exacerbation of the chemical imbalance causing CNS disorders.More specifically, mast cell degranulation is stimulated by commonneurotransmitters such as neurotensin, somatostatin, substance P andacetylcholine, by growth or survival factors, notably NGF, TGFβL Mastcells involved in the response to such stimulus can be brain mast cellsbut also other mast cells releasing the content of their granules in theblood stream that ultimately reach sensory, motor or brain neurons.Brain mast cells staining is CTMC staining-like but they show thesecretory pattern of MMC, implying that they constitute a particularsubset of mast cells presenting specificities.

Following mast cells activation, released granules liberate variousfactors capable of modulating and altering neurotransmission and neuronssurvival. Among such factors, serotonin is important since an increaseof the level of free serotonin has been observed in depressed patients.Alternatively, the sudden burst of serotonin may be followed by a periodof serotonin shortage, leading to pain and migraine. As a consequence,it is believed that mast cells exacerbate in autocrine or paracrinemanner the deregulation of neurotransmission. For example, anxiety orstress-induced release of neurotransmitters such as serotonin activatesmast cells, which in turn release the content of their granules, furthercontributing to the chemical imbalance in the brain leading to CNSdisorders.

Other mediators released by mast cells can be categorized intovasoactive, nociceptive, proinflammatory and other neurotransmitters.Taken together, these factors are able to induce great disturbance inthe activity of neurons, whether they are sensory, motor, or CNSneurons.

In addition, patients afflicted with mastocytosis are more incline todevelop CNS disorders than the normal population. This can be explainedby the presence of activating mutations in the c-kit receptor, whichinduce degranulation of mast cells and a burst of factors contributingto chemical imbalance and neurotransmission alteration.

In some cases, activated mast cells can also participate in thedestruction of neuronal tissues by releasing a cocktail of differentproteases and mediators categorized into three groups: preformedgranule-associated mediators (histamine, proteoglycans, and neutralproteases), lipid-derived mediators (prostaglandins, thromboxanes andleucotrienes), and various cytokines (IL-1, IL-2, IL-3, IL-4, IL-5,IL-6, IL-8, TNF-α, GM-CSF, MIP-LA, MIP-1b, MIP-2 and IFN-γ). Theliberation by activated mast cells of mediators (TNF-A, histamine,leukotrienes, prostaglandines etc.) as well as proteases may i) induceinflammation and vasodilatation and ii) participate in the neuronaltissue destruction process.

Inhibition of c-kit activity reduces cellular proliferation, depletingthe mast cells responsible for diseases and/or conditions, such asallergic diseases, thereby suggesting a role for use of inhibitors ofc-kit in the treatment of c-kit dependent diseases and/or conditions,such as CNS disorders. Described herein are diarylamine compounds,pharmaceutical compositions and medicaments, which include suchdiarylamine compounds or a pharmaceutically acceptable salt or solvatethereof, that are potent and selective c-kit inhibitors and whichselectively modulate, regulate, and/or inhibit signal transductionmediated by certain native and/or mutant tyrosine kinases implicated ina variety of human and animal diseases such as, by way of example only,CNS disorders.

Drug dependence is the result of a phenomenon called tolerance, which isthe need to increase the dose of the drug to maintain its full effect,and of physical dependence, which is the habituation of the body to adrug. When the intake of a drug is discontinued, individual mayexperience unpleasant withdrawal syndrome. This syndrome is difficult toqualify or quantify but it can be illustrated by a strong feeling ofunmet satisfaction.

This episode has been described by former drug addicted individuals as“a strong scream and complaint emanating from the body”, which indicatesthe seriousness and the difficulties encountered by these individuals.In addition, it must be emphasized that drug addiction is accompaniedwith or may follow psychiatric disorders such as anxiety, depression,and schizophrenia.

Drugs leading to dependence can be classified into two types. One typeis responsible for psychologic dependence such as cocaine, marijuana,amphetamine, and hallucinogens. The other type is more prone to physicaldependence, but one must not rule out psychologic dependence, and isexemplified by drugs such as heroin, alcohol and nicotine.

Of course, any drug that acts on the CNS may involve a risk ofdependence. For example, one of the side effects of benzodiazepinederivatives is dependence. In animal models, it has been observed thatadministration of drugs such as opioids, cocaine, amphetamine, nicotine,and benzodiazepines is associated with enhanced dopaminergictransmission. The problem is that the increased level of DA may befollowed by a down regulation of DA receptors. This might explain inpart the observed withdrawal symptoms that are sometimes associated withdepression, mood disorders, insomnia and other unwanted dependencedisorders.

Drug addiction may be responsible for, or arise from, job pressure orfamilial problems resulting in anxiety or depression. At the extreme ofthe spectrum, it can result in hospitalization for overdose, withdrawalepisodes and associated substance use disorders.

Finally, anxyolitics such as benzodiazepines are being consumed more andmore, therefore, it is urgent to find solutions for preventing andmanaging drug dependence and withdrawal symptoms. The socioeconomicconsequences of reliable solutions will have a huge impact in modernsocieties since addiction is often accompanied not only withsusceptibility to HIV infection and hepatitis. Consequently, researchprograms aimed at developing compounds capable of alleviating drugdependence and withdrawal symptoms must be encouraged and considered asa top priority.

Substance abuse and drug addiction introduce changes in neurotransmittersynthesis, storage, release, or in the number and affinity of receptors.This can affect neurotransmission and cause drug dependence andwithdrawal symptoms. Among neurotransmitters, example include, but arenot limited to, glutamate and aspartate, which are the major excitatoryneurotransmitters, aminobutyric acid (GABA), which is the majorinhibitory neurotransmitter in the brain and shown to be involved in thephysiopathology of depression; serotinin (5-HT); dopamine (DA), whichwas observed in depressed patients; acetylcholine, norepinephrine whichinteracts with adrenergic receptors and which is regulated by tyrosinehydroxylase and monoamine oxidase; endorphins, which are polypeptidesthat activate many central neurons and interact with opioid receptors,and others neurotransmitters such as enkephalins, dynorphins, histamine,vasopressin, vasoactive intestinal peptide, carnosine, bradykinin,cholecystokinin, bombesin, somatostatin, corticotropin releasing factor,neurotensin, and adenosine. As mentioned above, any imbalance in theseneurotransmitters or any deregulation of associated receptors due todrug intake may lead to the development of drug dependence andwithdrawal symptoms.

It has been identified that mast cells are involved in or contribute todrug dependence and withdrawal symptoms. The activation of mast cells bydifferent drugs, including, but not limited to, salicylic derivatives,morphine derivatives, opioids, heroin, amphetamines, alcohol, nicotine,analgesics, anesthetics, and anxyolitics results in the degranulation ofmast cells, which participate in the exacerbation of the chemicalimbalance responsible for drug habituation and withdrawal syndrome. Inaddition, following mast cells activation, released granules liberatevarious factors capable of modulating and altering neurotransmission.Among such factors, is morphine which is bound or stored in mast cellsgranules. Also tobacco smoke induces the release of mediators fromcanine mast cells and modulates prostaglandin production leading toasthma. In addition, patients afflicted with mastocytosis are moreincline to develop substance use disorders than the normal population.This can be explained by the presence of activating mutations in thec-kit receptor, which inducedegranulation of mast cells and a burst offactors contributing to chemical imbalance and neurotransmissionalteration.

Presently, there is no treatment providing relief and help toindividuals to withdraw from their addiction are available. C-kitinhibitors may be used for treating substance abuse disorders,particularly drug addiction, drug abuse, drug habituation, drugdependence, withdrawal syndrome and overdose, comprising administering acompound capable of depleting mast cells to a human in need of suchtreatment.

Inhibition of c-kit activity reduces cellular proliferation, depletingthe mast cells responsible for diseases and/or conditions, such as drugdependency, thereby suggesting a role for use of inhibitors of c-kit inthe treatment of c-kit dependent diseases and/or conditions, such asdrug dependency. Described herein are diarylamine compounds,pharmaceutical compositions and medicaments, which include suchdiarylamine compounds or a pharmaceutically acceptable salt or solvatethereof, that are potent and selective c-kit inhibitors and whichselectively modulate, regulate, and/or inhibit signal transductionmediated by certain native and/or mutant tyrosine kinases implicated ina variety of human and animal diseases such as, by way of example only,drug dependency.

Described herein are diarylamine compounds, pharmaceutical compositionsand medicaments, which include such diarylamine compounds or apharmaceutically acceptable salt or solvate thereof, for treating adisease and/or condition in an animal in which c-kit receptor activitycontributes to the pathology and/or symptomology of the disease orcondition. Such diseases and/or conditions include, but are not limitedto, (i) neoplastic diseases, such as, but not limited to mastocytosis,canine mastocytoma, human gastrointestinal stromal tumor, small celllung cancer, non-small cell lung cancer, acute myelocytic leukemia,acute lymphocytic leukemia, myelodysplastic syndrome, chronicmyelogenous leukemia, colorectal carcinomas, gastric carcinomas,gastrointestinal stromal tumors, testicular cancers, glioblastomas, andastrocytomas; (ii) allergy diseases, such as, but not limited to,asthma, allergic rhinitis, allergic sinusitis, anaphylactic syndrome,urticaria, angioedema, atopic dermatitis, allergic contact dermatitis,erythema nodosum, erythema multiforme, cutaneous necrotizing venulitisand insect bite skin inflammation and blood sucking parasiticinfestation; (iii) inflammatory diseases, such as, but not limited to,rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions; (iv)autoimmune diseases, such as, but not limited to, multiple sclerosis,psoriasis, intestine inflammatory disease, ulcerative colitis, Crohn'sdisease, rheumatoid arthritis and polyarthritis, local and systemicscleroderma, systemic lupus erythematosus, discoid lupus erythematosus,cutaneous lupus, dermatomyositis, polymyositis, Sjogren's syndrome,nodular panarteritis, autoimmune enteropathy, and proliferativeglomerulonephritis; (v) graft-versus-host diseases, such as, but notlimited to, organ transplantation graft rejection (including, but notlimited to, kidney transplantation, pancreas transplantation, livertransplantation, heart transplantation, lung transplantation, and bonemarrow transplantation); (vi) metabolic syndromes, such as, but notlimited to, type I diabetes, type II diabetes, or obesity; (vii) CNSrelated disorders, such as, but not limited to, depression, dysthymicdisorder, cyclothymic disorder, bipolar depression, severe or“melancholic” depression, atypical depression, refractory depression,seasonal depression, anorexia, bulimia, premenstrual syndrome andpost-menopause syndrome, as mental slowing and loss of concentration,pessimistic worry, agitation, self-deprecation and decreased libido, asanxiety disorders including anxiety associated with hyperventilation andcardiac arrhythmias, phobic disorders, obsessive-compulsive disorder,posttraumatic stress disorder, acute stress disorder, and generalizedanxiety disorder, as psychiatric disorders such as panic attacks,including psychosis, delusional disorders, conversion disorders,phobias, mania, delirium, dissociative episodes including dissociativeamnesia, dissociative fugue and dissociative suicidal behavior,self-neglect, violent or aggressive behavior, trauma, borderlinepersonality, and acute psychosis as schizophrenia including paranoidschizophrenia, disorganized schizophrenia, catatonic schizophrenia, andundifferentiated schizophrenia; (viii) neurodegenerative diseases, suchas, but not limited to, Alzheimer's disease, Parkinson's disease,Huntington's disease, the prion diseases, Motor Neuron Disease (MND),and Amyotrophic Lateral Sclerosis (ALS), (ix) pain, such as, but notlimited to, acute pain, postoperative pain, chronic pain, nociceptivepain, cancer pain, neuropathic pain, and psychogenic pain syndromes; (x)substance use disorders, such as, but not limited to, drug addiction,drug abuse, drug habituation, drug dependence, withdrawal syndrome andoverdose; (xi) prion diseases; (xii) cancers, such as, but not limitedto, melanoma, gastrointestinal stromal tumor (GIST), small-cell lungcancer, germ cell tumors, mast cell tumors, breast cancer, acutemyelogenous leukemia, neuroblastoma, mastocytosis, and other solidtumors; (xiii) heart diseases; (xiv) fibrotic diseases, such as, but notlimited to, hepatitis C (HCV), liver fibrosis, nonalcoholicsteatohepatitis (NASH), cirrhosis in liver, pulmonary fibrosis, and bonemarrow fibrosis; (xv) idiopathic pulmonary arterial hypertension (IPAH);and (xvi) primary pulmonary hypertension (PPH).

Compounds

Compounds having the structure of Formula (A) or Formula (B),pharmaceutically acceptable salts, pharmaceutically acceptable N-oxides,pharmaceutically active metabolites, pharmaceutically acceptableprodrugs, and pharmaceutically acceptable solvates thereof, modulate theactivity of c-kit receptors; and, as such, are useful for treatingdiseases or conditions in which aberrant c-kit receptor activitycontributes to the pathology and/or symptoms of a disease or condition:

wherein:

-   -   Q₁ is H, halogen, a group comprising a non-aromatic tertiary        amine, a group comprising a non-aromatic secondary amine, or is        an optionally substituted moiety selected from the group        consisting of: -L-alkyl, -L-cycloalkyl, -L-heteroalkyl,        -L-haloalkyl, -L-aryl, -L-heterocycloalkyl, and -L-heteroaryl;        wherein L is selected from a bond, —O—, —NH—, —S—, —C(O)—,        —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —OC(O)—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″YC(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y is optionally substituted        arylene or heteroarylene;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L₁-heteroaryl; wherein L₁        is selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—,        —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—,        —OC(O)—, —CR″₂NR″CR″₂C(O)O—, —C(O)—NR″Y¹C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y¹ is optionally        substituted arylene or heteroarylene;    -   Q₂ is selected from the group consisting of H, halogen, and a        group comprising an optionally substituted moiety selected from        -L₆-alkyl, -L₆-cycloalkyl, -L₆-heteroalkyl, -L₆-haloalkyl,        -L₆-aromatic carbocycle, -L₆-heterocycloalkyl, and -L₆-aromatic        heterocycle; wherein L₆ is selected from a bond, —O—, —NH—, —S—,        —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—, —S(O)₂—,        —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,        —C(O)—NR″Y″C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; and Y″ is        optionally substituted arylene or heteroarylene;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        haloaryl, or heteroaryl;    -   any two R₁ groups together may form an optionally substituted 5        to 8-membered heterocyclic, cycloalkyl, or aryl ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl, wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring.

Compounds having the structure of Formula (A) or Formula (B) includecompounds having the structure of Formula (1) or Formula (46) andpharmaceutically acceptable salts, pharmaceutically acceptable N-oxides,pharmaceutically active metabolites, pharmaceutically acceptableprodrugs, and pharmaceutically acceptable solvates thereof. Suchcompounds also modulate the activity of c-kit receptors and, as such,are useful for treating diseases or conditions in which aberrant c-kitreceptor activity contributes to the pathology and/or symptoms of adisease or condition:

wherein:

-   -   Ar is a group comprising a moiety selected from an optionally        substituted five-membered aromatic heterocycle, an optionally        substituted five-membered aromatic carbocycle, an optionally        substituted six-membered aromatic heterocycle, and a        substituted, optionally further substituted six-membered        aromatic carbocycle;    -   Q is a group comprising a non-aromatic tertiary amine or a        non-aromatic secondary amine, with the proviso that Q is not        —NR_(a)R_(B) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b)        is independently H or C₁₋₆alkyl optionally substituted by mono-        or di-alkyl (C₁₋₆) amino;    -   each R₁ is independently selected from the group consisting of        H, halogen, and an optionally substituted moiety selected from        -L₁-alkyl, -L₁-cycloalkyl, -L₁-heteroalkyl, -L₁-haloalkyl,        -L₁-aryl, -L₁-heterocycloalkyl, and -L-heteroaryl; wherein L₁ is        selected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—,        —C(O)NH—, —S(O)—, —S(O)₂—, —C(O)NH(CR″₂)₁₋₆C(O)O—,        —C(O)NR″NR″C(O)O—, and —S(O)NH—;    -   each R″ is independently H, OH, halogen, C₁₋₆alkyl, substituted        C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl,        halo aryl, or heteroaryl;    -   or any two adjacent R₁ groups together may form an optionally        substituted 5 to 8-membered heterocyclic, cycloalkyl, or aryl        ring;    -   R₅ is selected from the group consisting of H, and an optionally        substituted moiety selected from -L₅-H, -L₅-alkyl,        -L₅-cycloalkyl, -L₅-heteroalkyl, -L₅-haloalkyl, -L₅-aryl,        -L₅-heterocycloalkyl, and -L₅-heteroaryl; wherein L₅ is selected        from a bond, —R′O—, —R′N(H)—, —R′S—, —R′C(O)—, —R′C(S)—,        —R′C(O)O—, and —R′C(O)NH—;    -   each R′ is independently selected from the group consisting of a        bond, alkylene, substituted alkylene, heteroalkylene,        substituted heteroalkylene, alkenylene, substituted alkenylene,        cycloalkylene, substituted cycloalkylene, heteroalkylene,        substituted heteroalkylene, heterocycloalkylene, substituted        heterocycloalkylene, arylene, substituted arylene,        heteroarylene, substituted heteroarylene, alkarylene,        substituted alkarylene, aralkylene, and substituted aralkylene;        and    -   any R₁ and R₅ taken together may form an optionally substituted        5 to 8-membered heterocyclic, cycloalkyl, or aryl ring.

Table 1 shows exemplary, non-limiting examples of compounds which havethe structure of Formula (A) or Formula (B), and which modulate theactivity of c-kit receptors.

Table 1: Exemplary Compounds which Modulate the Activity of c-kitReceptors.

TABLE 1 Examplary compounds which modulate the activity of c-kitreceptors. MS # Structure [M + 1]⁺ 1

520.4 2

582.4 3

536.4 4

520.4 5

538.3 6

542.3 7

498.3 8

572.3 9

600.4 10

570.5 11

574.4 12

492.4 13

568.4 14

520.4 15

582.4 16

536.4 17

520.4 18

524.5 19

506.5 20

521.2 21

425.1 22

433.2 23

520.5 24

447.2 25

377.2 26

627.0 27

534.5 28

631.6 29

421.2 30

425.5 31

423.1 32

423.4 33

492.3 34

552.2 35

552.1 36

379.2 37

453.1 38

550.2 39

534.2 40

504.3 41

391.2 42

391.2 43

395.2 44

377.4 45

421.2 46

605.1 47

517.5 48

580.3 49

449.2 50

550.1 51

379.2 52

393.4 53

534.2 54

534.5 55

522.2 56

638.0 57

494.3 58

463.1 59

506.2 60

582.6 61

575.1 62

575.1 63

562.2 64

548.6 65

423.1 66

391.3 67

534.2 68

631.0 69

365.2 70

477.0 71

592.0 72

453.1 73

448.3 74

421.1 75

548.5 76

494.1 77

621.0 78

591.1 79

532.3 80

448.3 81

421.2 82

590.1 83

465.5 84

364.2 85

464.3 86

560.2 87

580.1 88

560.5 89

407.2 90

647.0 91

604.0 92

435.0 93

407.2 94

548.1 95

506.2 96

425.2 97

575.1 98

611.0 99

604.1 100

558.1 101

519.2 102

484.3 103

518.3 104

549.2 105

406.4 106

619.0 107

516.2 108

422.3 109

389.2 110

433.3 111

420.4 112

431.1 113

608.0 114

646.0 115

428.1 116

349.1 117

647.0 118

500.3 119

547.1 120

504.3 121

485.2 122

608.3 123

505.3 124

582.3 125

562.5 126

647.4 127

610.0 128

369.1 129

406.4 130

409.4 131

394.2 132

421.2 133

508.2 134

411.2 135

492.4 136

568.4 137

542.3 138

471.3 139

408.3 140

465.0 141

520.3 142

383.1 143

407.1 144

420.3 145

406.2 146

448.3 147

617.5 148

549.4 149

558.3 150

632.4 151

618.4 152

675.5 153

633.4 154

393.2 155

451.3 156

437.2 157

377.3 158

409.2 159

441.2 160

432.3 161

403.0 162

444.3 163

420.0 164

418.5 165

361.3 166

405.2 167

447.3 168

470.0 169

418.2 170

346.2 171

435.0 172

376.0 173

407.2 174

462.0 175

418.3 176

474.3 177

391.3 178

432.3 179

389.4 180

476.3 181

419.0 182

391.0 183

476.3 184

432.3 185

405.3 186

377.3 187

405.3 188

433.0 189

419.0 190

434.3 191

461.3 192

476.3 193

347.3 194

448.3 195

405.0 196

433.0 197

446.2 198

431.2 199

419.2 200

389.2 201

488.3 202

419.2 203

518.3 204

601.3 205

434.0 206

533.0 207

533.1 208

478.3 209

478.2 210

420.5 211

407.2 212

365.2 213

434.3 214

418.3 215

419.3 216

419.1 217

390.5 218

406.2 219

404.2 220

420.2 221

418.6 222

413.5 223

392.5 224

447.6 225

447.2 226

416.2 227

434.2 228

307.1 229

433.2 230

390.3 231

432.4 232

488.4 233

432.3 234

461.4 235

484.4 236

432.3 237

404.2 238

432.4 239

417.4 240

434.4 241

405.4 242

419.2 243

375.3 244

418.4 245

375.3 246

405.1 247

391.4 248

419.3 249

447.3 250

445.3 251

477.2 252

437.2 253

447.3 254

469.3 255

461.3 256

435.2 257

437.2 258

432.2 259

473.5 260

447.2 261

433.5 262

461.3 263

475.3 264

448.2 265

490.4 266

476.3 267

490.3 268

473.3 269

433.2 270

462.3 271

421.2 272

419.1 273

435.2 274

435.2 275

461.1 276

447.2 277

433.2 278

445.2 279

491.2 280

447.2 281

447.2 282

533.2 283

465.2 284

451.2 285

431.2 286

499.2 287

419.2 288

419.2 289

403.3 290

432.2 291

419.2 292

490.2 293

391.2 294

375.2 295

488.3 296

419.2 297

391.2 298

379.3 299

405.1 300

419.2 301

401.2 302

367.1 303

441.2 304

375.2 305

419.2 306

448.3 307

415.2 308

403.2 309

484.3 310

446.2 311

432.3 312

418.3 313

379.2 314

392.2 315

389.2 316

432.2 317

398.2 318

440.2 319

467.2 320

405.2 321

377.2 322

441.2 323

440.2 324

425.2 325

429.3 326

491.2 327

486.3 328

482.2 329

472.4 330

393.1 331

426.3 332

365.2 333

405.2 334

405.2 335

401.2 336

405.2 337

458.4 338

403.2 339

421.2 340

389.2 341

458.4 342

426.2 343

432.2 344

378.2 345

403.2 346

432.2 347

458.5 348

419.5 349

464.2 350

417.3 351

429.2 352

435.3 353

393.2 354

478.3 355

421.3 356

447.3 357

379.2 358

405.2 359

367.2 360

385.2 361

448.3 362

415.3 363

484.3 364

446.3 365

432.3 366

418.3 367

379.2 368

392.3 369

432.2 370

398.2 371

467.3 372

429.2 373

491.3 374

486.3 375

482.5 376

472.3 377

426.3 378

365.2 379

405.3 380

405.3 381

458.2 382

432.2 383

405.3 384

405.2 385

389.3 386

458.4 387

426.3 388

432.3 389

403.3 390

432.3 391

432.3 392

458.3 393

419.3 394

429.5 395

393.3 396

392.1 397

403.6 398

501.6 399

487.3 400

503.3 401

474.6 402

475.5 403

501.5 404

440.3 405

486.6 406

453.1 407

426.3 408

460.4 409

440.7 410

432.5 411

375.5 412

391.3 413

390.1 414

404.2 415

391.2 416

390.1 417

404.2 418

391.2 419

432.2 420

462.2 421

448.2 422

483.2 423

458.2 424

433.2 425

475.2 426

490.2 427

447.2 428

462.2 429

448.2 430

407.1 431

375.1 432

433.3 433

447.2 434

502.4 435

463.2 436

505.3 437

445.2 438

391.2 439

391.2

Synthesis of the Compounds

Compounds of Formula (A) or Formula (B) and compounds having thestructures described in the prior section may be synthesized usingstandard synthetic techniques known to those of skill in the art orusing methods known in the art in combination with methods describedherein. In additions, solvents, temperatures and other reactionconditions presented herein may vary according to the practice andknowledge of those of skill in the art.

The starting material used for the synthesis of the compounds of Formula(A) or Formula (B) and compounds having the structures described in theprior section as described herein can be obtained from commercialsources, such as Aldrich Chemical Co. (Milwaukee, Wis.), Sigma ChemicalCo. (St. Louis, Mo.), or the starting materials can be synthesized. Thecompounds described herein, and other related compounds having differentsubstituents can be synthesized using techniques and materials known tothose of skill in the art, such as described, for example, in March,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Carey and Sundberg,ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., Vols. A and B (Plenum 2000,2001), and Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3^(rd)Ed., (Wiley 1999) (all of which are incorporated by reference in theirentirety). General methods for the preparation of compound as disclosedherein may be derived from known reactions in the field, and thereactions may be modified by the use of appropriate reagents andconditions, as would be recognized by the skilled person, for theintroduction of the various moieties found in the formulae as providedherein. As a guide the following synthetic methods may be utilized.

Formation of Covalent Linkages by Reaction of an Electrophile with aNucleophile

The compounds described herein can be modified using variouselectrophiles or nucleophiles to form new functional groups orsubstituents. Table 2 entitled “Examples of Covalent Linkages andPrecursors Thereof” lists selected examples of covalent linkages andprecursor functional groups which yield and can be used as guidancetoward the variety of electrophiles and nucleophiles combinationsavailable. Precursor functional groups are shown as electrophilic groupsand nucleophilic groups.

TABLE 2 Examples of Covalent Linkages and Precursors Thereof CovalentLinkage Product Electrophile Nucleophile Carboxamides Activated estersamines/anilines Carboxamides acyl azides amines/anilines Carboxamidesacyl halides amines/anilines Esters acyl halides alcohols/phenols Estersacyl nitriles alcohols/phenols Carboxamides acyl nitrilesamines/anilines Imines Aldehydes amines/anilines Hydrazones aldehydes orketones Hydrazines Oximes aldehydes or ketones Hydroxylamines Alkylamines alkyl halides amines/anilines Esters alkyl halides carboxylicacids Thioethers alkyl halides Thiols Ethers alkyl halidesalcohols/phenols Thioethers alkyl sulfonates Thiols Esters alkylsulfonates carboxylic acids Ethers alkyl sulfonates alcohols/phenolsEsters Anhydrides alcohols/phenols Carboxamides Anhydridesamines/anilines Thiophenols aryl halides Thiols Aryl amines aryl halidesAmines Thioethers Azindines Thiols Boronate esters Boronates GlycolsCarboxamides carboxylic acids amines/anilines Esters carboxylic acidsAlcohols hydrazines Hydrazides carboxylic acids N-acylureas orAnhydrides carbodiimides carboxylic acids Esters diazoalkanes carboxylicacids Thioethers Epoxides Thiols Thioethers haloacetamides ThiolsAmmotriazines halotriazines amines/anilines Triazinyl ethershalotriazines alcohols/phenols Amidines imido esters amines/anilinesUreas Isocyanates amines/anilines Urethanes Isocyanates alcohols/phenolsThioureas isothiocyanates amines/anilines Thioethers Maleimides ThiolsPhosphite esters phosphoramidites Alcohols Silyl ethers silyl halidesAlcohols Alkyl amines sulfonate esters amines/anilines Thioetherssulfonate esters Thiols Esters sulfonate esters carboxylic acids Etherssulfonate esters Alcohols Sulfonamides sulfonyl halides amines/anilinesSulfonate esters sulfonyl halides phenols/alcohols

Use of Protecting Groups

In the reactions described, it may be necessary to protect reactivefunctional groups, for example hydroxy, amino, imino, thio or carboxygroups, where these are desired in the final product, to avoid theirunwanted participation in the reactions. Protecting groups are used toblock some or all reactive moieties and prevent such groups fromparticipating in chemical reactions until the protective group isremoved. It is preferred that each protective group be removable by adifferent means. Protective groups that are cleaved under totallydisparate reaction conditions fulfill the requirement of differentialremoval. Protective groups' can be removed by acid, base, andhydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal andt-butyldimethylsilyl are acid labile and may be used to protect carboxyand hydroxy reactive moieties in the presence of amino groups protectedwith Cbz groups, which are removable by hydrogenolysis, and Fmoc groups,which are base labile. Carboxylic acid and hydroxy reactive moieties maybe blocked with base labile groups such as, but not limited to, methyl,ethyl, and acetyl in the presence of amines blocked with acid labilegroups such as t-butyl carbamate or with carbamates that are both acidand base stable but hydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester compounds as exemplifiedherein, or they may be blocked with oxidatively-removable protectivegroups such as 2,4-dimethoxybenzyl, while co-existing amino groups maybe blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pdo-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups, plus a detailed description of techniquesapplicable to the creation of protecting groups and their removal aredescribed in Greene and Wuts, Protective Groups in Organic Synthesis,3rd Ed., John Wiley & Sons, New York, N.Y., 1999, and Kocienski,Protective Groups, Thieme Verlag, New York, N.Y., 1994, which areincorporated herein by reference in their entirety.

Compounds of Formula (1) can be synthesized according to reaction scheme1a, wherein amine compounds (A) react with dihalogen compounds (B) togive diaryl compounds (C). Arylation of compounds (C) yield compounds(1).

Arylation, by way of example only, may be accomplished by reaction ofthe halogen functionality with an aryl derivatized boronic acid in thepresence of tetrakis(triphenylphosphino) palladium.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1b, wherein halogen compounds (D) react with aminecompounds (E) to give diaryl compounds of (C). Arylation of compounds(C) yield compounds (1).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1c, wherein halogen compounds (B) react with aminecompounds (a″) to give diaryl compounds (c″). Arylation of compounds(c″) yield compounds (1-C), and subsequent amination affords compounds(1).

wherein, Z is CR₁R1, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted). Amination, by way of example only, maybe accomplished by reaction of the halogen functionality with anappropriate amine.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1 d, wherein halogen compounds (d″) react with aminecompounds (E) to give diaryl compounds (c″). Arylation of compounds (c″)yield compounds (1-C), and subsequent amination affords compounds (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1e, wherein dihalogen compounds (B) are arylated to givecompounds (b″). Compounds (b″) are then reacted with amine compounds (A)to yield compounds (1).

Arylation, by way of example only, may be accomplished by reaction ofthe halogen functionality with an aryl derivatized boronic acid in thepresence of tetrakis(triphenylphosphino) palladium.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme if, wherein compounds (E) are arylated to give compounds(e″). Compounds (e″) are then reacted with amine compounds (D) to yieldcompounds (1);

Arylation, by way of example only, may be accomplished by reaction ofthe halogen functionality with an aryl derivatized boronic acid in thepresence of tetrakis(triphenylphosphino) palladium.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1g, wherein dihalogen compounds (B) are arylated givingcompounds (b″), which then react with amine compounds (a″) to givecompounds (1-C). Subsequent amination of compounds (1-C) affordscompounds (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted). Arylation, by way of example only, maybe accomplished by reaction of the halogen functionality with an arylderivatized boronic acid in the presence of tetrakis(triphenylphosphino)palladium. Amination, by way of example only, may be accomplished byreaction of the halogen functionality with an appropriate amine.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 1 h, wherein halogen compounds (E) are arylated givingcompounds (e″), which then react with amine compounds (d″) to givecompounds (1-C). Subsequent amination of compounds (1-C) affordscompounds (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted). Arylation, by way of example only, maybe accomplished by reaction of the halogen functionality with an arylderivatized boronic acid in the presence of tetrakis(triphenylphosphino)palladium. Amination, by way of example only, may be accomplished byreaction of the halogen functionality with an appropriate amine.

Similarly, compounds of Formula (1) can be synthesized according toreaction scheme 2a, wherein substituted amine compounds (F) react withdihalogen compounds (B) to give diaryl compounds (H). Arylation ofcompounds (H) yield compounds (1).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2b, wherein halogen compounds (D) react with substitutedamine compounds (1) to give diaryl compounds (H). Arylation of compounds(H) yield compounds of Formula (1).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2c, wherein halogen compounds (B) react with aminecompounds (f″) to give diaryl compounds (h″). Arylation of compounds(h″) yield compounds (2-C), and subsequent amination affords compoundsof Formula (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2d, wherein halogen compounds (d″) react with aminecompounds (E) to give diaryl compounds (c″). Arylation of compounds (c″)yield compounds (1-D), and subsequent amination affords compounds ofFormula (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted).

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2e, wherein dihalogen compounds (B) are arylated to givecompounds (b″), which react with substituted amine compounds (F) toyield compounds of Formula (1).

Arylation, by way of example only, may be accomplished by reaction ofthe halogen functionality with an aryl derivatized boronic acid in thepresence of tetrakis(triphenylphosphino) palladium.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2f, wherein compounds (1) are arylated to give compounds(i″). Compounds (i″) are then reacted with amine compounds (D) to yieldcompounds of Formula (1).

Arylation, by way of example only, may be accomplished by reaction ofthe halogen functionality with an aryl derivatized boronic acid in thepresence of tetrakis(triphenylphosphino) palladium.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2g, wherein dihalogen compounds (B) are arylated givingcompounds (b″), which then react with amine compounds (f″) to givecompounds (2-C). Subsequent amination of compounds (2-C) affordscompounds of Formula (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted). Arylation, by way of example only, maybe accomplished by reaction of the halogen functionality with an arylderivatized boronic acid in the presence of tetrakis(triphenylphosphino)palladium. Amination, by way of example only, may be accomplished byreaction of the halogen functionality with an appropriate amine.

Alternatively, compounds of Formula (1) can be synthesized according toreaction scheme 2h, wherein halogen compounds (1) are arylated givingcompounds (i″), which then react with amine compounds (d″) to givecompounds (2-C). Subsequent amination of compounds (2-C) affordscompounds of Formula (1).

wherein, Z is CR₁R₁, O, or S, and L is alkylene (substituted orunsubstituted), alkenylene (substituted or unsubstituted),heteroalkylene (substituted or unsubstituted), or heteroalkenylene(substituted or unsubstituted). Arylation, by way of example only, maybe accomplished by reaction of the halogen functionality with an arylderivatized boronic acid in the presence of tetrakis(triphenylphosphino)palladium. Amination, by way of example only, may be accomplished byreaction of the halogen functionality with an appropriate amine.

The synthesis of amine compounds (A), compounds (a″), compounds (F) andcompounds (f″) may be accomplished according to reaction schemes andmethodologies known to one skilled in the art used to obtain aminecontaining compounds. By way of example only, a synthesis of aminecompounds (A) is shown in reaction scheme 3a, wherein formation ofpara-substituted nitrobenzenes results from the addition of halogencontaining compounds with reactive nitrobenzenes. Subsequent reductionof such para-substituted nitrobenzene compounds affords amine compounds(A).

wherein L is alkylene (substituted or unsubstituted), alkenylene(substituted or unsubstituted), heteroalkylene (substituted orunsubstituted), or heteroalkenylene (substituted or unsubstituted).Reduction, by way of example only, may be accomplished using hydrogenwith palladium on carbon as a catalyst.

By way of example only, a synthesis of amine compounds (a″) is shown inreaction scheme 3b, wherein formation of para-substituted nitrobenzenecompounds containing terminal halogens results from the addition ofdi-halogen containing compounds with reactive nitrobenzenes. Subsequentreduction of such para-substituted nitrobenzene compounds affordscompounds (a″).

wherein L is alkylene (substituted or unsubstituted), alkenylene(substituted or unsubstituted), heteroalkylene (substituted orunsubstituted), or heteroalkenylene (substituted or unsubstituted).

By way of example only, a synthesis of amine compounds (A) is shown inreaction scheme 3c, wherein formation of para-substituted protectedanilines results from the addition of halogen containing compounds withreactive protected anilines. Subsequent deprotection of suchpara-substituted protected anilines compounds affords amine compounds(A).

wherein L is alkylene (substituted or unsubstituted), alkenylene(substituted or unsubstituted), heteroalkylene (substituted orunsubstituted), or heteroalkenylene (substituted or unsubstituted).

By way of example only, a synthesis of amine compounds (F) is shown inreaction scheme 3d, wherein formation of para-substituted nitrobenzenesresults from the addition of halogen containing compounds with areactive nitrobenzene. Reduction of such para-substituted nitrobenzenecompounds affords amine compounds (A) and subsequent alkylation of theyields substituted amine compounds (F).

wherein L is alkylene (substituted or unsubstituted), alkenylene(substituted or unsubstituted), heteroalkylene (substituted orunsubstituted), or heteroalkenylene (substituted or unsubstituted).

By way of example only, a synthesis of amine compounds (f″) is shown inreaction scheme 3e, wherein formation of para-substituted nitrobenzenescompounds containing terminal halogens results from the addition ofdi-halogen containing compounds with a reactive nitrobenzene. Reductionof such para-substituted nitrobenzene compounds affords compounds (a″)and subsequent alkylation of the yields substituted amine compounds(f″).

wherein L is alkylene (substituted or unsubstituted), alkenylene(substituted or unsubstituted), heteroalkylene (substituted orunsubstituted), or heteroalkenylene (substituted or unsubstituted).

The pyrimidine compounds (B), compounds (E) and compounds (I) may besynthesized according to reaction schemes and methodologies known to oneskilled in the art, or alternatively they may be purchased. By way ofexample only, various pyrimidine compounds may be obtained using PinnerPyrimidine Synthesis as shown in reaction scheme 4a,

wherein R₁ and R₂ are independently selected from H, halogen, alkyl,heteroalkyl, cycloalkyl, heterocyloalkyl, aryl and heteroaryl; R₃ isNH₂, SH, alkyl, or halogen, or the N—C—N type reagent may be urea. Thisapproach may be used in the synthesis of amine compounds (E) as shown inreaction scheme 4b

and the approach may be used to synthesize 2-amino-5-bromopyrimidine asshown in reaction scheme 4c;

Similarly, amine compounds (1) may be synthesized as shown in reactionscheme 4d and reaction scheme 4e,

and to synthesize 2-chloro-5-bromopyrimidine as shown in reaction scheme4c;

Further Forms of Compounds

For convenience, the form and other characteristics of the compoundsdescribed in this section and other parts herein use a single formula,such as “Formula (A) or Formula (B),” by way of example. However, theform and other characteristics of the compounds described herein applyequally well to all formulas presented herein that fall within the scopeof Formula (A) or Formula (B). For example, the form and othercharacteristics of the compounds described herein can be applied tocompounds having the structure of any of Formula (1) to Formula (54), aswell as to all of the specific compounds that fall within the scope ofthese generic formula.

Compounds of Formula (A) or Formula (B) can be prepared as apharmaceutically acceptable salts formed when an acidic proton presentin the parent compound either is replaced by a metal ion, for example analkali metal ion, an alkaline earth ion, or an aluminum ion; orcoordinates with an organic base. In addition, the salt forms of thedisclosed compounds can be prepared using salts of the startingmaterials or intermediates.

Compounds of Formula (A) or Formula (B) can be prepared as apharmaceutically acceptable acid addition salt (which is a type of apharmaceutically acceptable salt) by reacting the free base form of thecompound with a pharmaceutically acceptable inorganic or organic acid,including, but not limited to, inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acidmetaphosphoric acid, and the like; and organic acids such as aceticacid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, Q-toluenesulfonic acid, tartaricacid, trifluoroacetic acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid,1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, 2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4′-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, and muconic acid.

Alternatively, compounds of Formula (A) or Formula (B) can be preparedas a pharmaceutically acceptable base addition salts (which is a type ofa pharmaceutically acceptable salt) by reacting the free acid form ofthe compound with a pharmaceutically acceptable inorganic or organicbase, including, but not limited to organic bases such as ethanolamine,diethanolamine, triethanolamine, tromethamine, N-methylglucamine, andthe like and inorganic bases such as aluminum hydroxide, calciumhydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, andthe like.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and may beformed during the process of crystallization with pharmaceuticallyacceptable solvents such as water, ethanol, and the like. Hydrates areformed when the solvent is water, or alcoholates are formed when thesolvent is alcohol. Solvates of compounds of Formula (A) or Formula (B)can be conveniently prepared or formed during the processes describedherein. By way of example only, hydrates of compounds of Formula (A) orFormula (B) can be conveniently prepared by recrystallization from anaqueous/organic solvent mixture, using organic solvents including, butnot limited to, dioxane, tetrahydrofuran or methanol. In addition, thecompounds provided herein can exist in unsolvated as well as solvatedforms. In general, the solvated forms are considered equivalent to theunsolvated forms for the purposes of the compounds and methods providedherein.

Compounds of Formula (A) or Formula (B) include crystalline forms, alsoknown as polymorphs. Polymorphs include the different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability, and solubility. Various factors such as therecrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

Compounds of Formula (A) or Formula (B) in unoxidized form can beprepared from N-oxides of compounds of Formula (A) or Formula (B) bytreating with a reducing agent, such as, but not limited to, sulfur,sulfur dioxide, triphenyl phosphine, lithium borohydride, sodiumborohydride, phosphorus trichloride, tribromide, or the like in asuitable inert organic solvent, such as, but not limited to,acetonitrile, ethanol, aqueous dioxane, or the like at 0 to 80° C.

Compounds of Formula (A) or Formula (B) can be prepared as prodrugs.Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs are often usefulbecause, in some situations, they may be easier to administer than theparent drug. They may, for instance, be bioavailable by oraladministration whereas the parent is not. The prodrug may also haveimproved solubility in pharmaceutical compositions over the parent drug.An example, without limitation, of a prodrug would be a compound ofFormula (A) or Formula (B) which is administered as an ester (the“prodrug”) to facilitate transmittal across a cell membrane where watersolubility is detrimental to mobility but which then is metabolicallyhydrolyzed to the carboxylic acid, the active entity, once inside thecell where water-solubility is beneficial. A further example of aprodrug might be a short peptide (polyaminoacid) bonded to an acid groupwhere the peptide is metabolized to reveal the active moiety.

Prodrugs may be designed as reversible drug derivatives, for use asmodifiers to enhance drug transport to site-specific tissues. The designof prodrugs to date has been to increase the effective water solubilityof the therapeutic compound for targeting to regions where water is theprincipal solvent. See, e.g., Fedorak et al., Am. J. Physiol.,269:G210-218 (1995); McLoed et al., Gastroenterol, 106:405-413 (1994);Hochhaus et al., Biomed. Chrom., 6:283-286 (1992); J. Larsen and H.Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int.J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci.,64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche,Bioreversible Carriers in Drug Design, American PharmaceuticalAssociation and Pergamon Press, 1987, all incorporated herein in theirentirety.

Additionally, prodrug derivatives of compounds of Formula (A) or Formula(B) can be prepared by methods known to those of ordinary skill in theart (e.g., for further details see Saulnier et al., (1994), Bioorganicand Medicinal Chemistry Letters, Vol. 4, p. 1985). By way of exampleonly, appropriate prodrugs can be prepared by reacting a non-derivatizedcompound of Formula (A) or Formula (B) with a suitable carbamylatingagent, such as, but not limited to, 1,1-acyloxyalkylcarbanochloridate,para-nitrophenyl carbonate, or the like. Prodrug forms of the hereindescribed compounds, wherein the prodrug is metabolized in vivo toproduce a derivative as set forth herein are included within the scopeof the claims. Indeed, some of the herein-described compounds may be aprodrug for another derivative or active compound.

Sites on the aromatic ring portion of compounds of Formula (A) orFormula (B) can be susceptible to various metabolic reactions, thereforeincorporation of appropriate substituents on the aromatic ringstructures, such as, by way of example only, halogens can reduce,minimize or eliminate this metabolic pathway.

Compounds of Formula (A) or Formula (B) can be optically pureenantiomers or a racemic mixture. Compounds of Formula (A) or Formula(B) can be prepared as their individual stereoisomers by reacting aracemix mixture of the compound with an optically active resolving agentto form a pair of diastereoisomeric compounds, separating thediastereomers and recovering the optically pure enentiomers.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by another other means, including, but not limited to,the use of chromophores or fluorescent moieties, bioluminescent labels,or chemiluminescent labels. The compounds of Formula (A) or Formula (B)may possess one or more chiral centers and each center may exist in theR or S configuration. The compounds presented herein include alldiastereomeric, enantiomeric, and epimeric forms as well as theappropriate mixtures thereof. Compounds of Formula (A) or Formula (B)can be prepared as their individual stereoisomers by reacting a racemicmixture of the compound with an optically active resolving agent to forma pair of diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. While resolution ofenantiomers can be carried out using covalent diastereomeric derivativesof the compounds described herein, dissociable complexes are preferred(e.g., crystalline diastereomeric salts). Diastereomers have distinctphysical properties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and can be readily separated by taking advantage ofthese dissimilarities. The diastereomers can be separated by chiralchromatography, or preferably, by separation/resolution techniques basedupon differences in solubility. The optically pure enantiomer is thenrecovered, along with the resolving agent, by any practical means thatwould not result in racemization. A more detailed description of thetechniques applicable to the resolution of stereoisomers of compoundsfrom their racemic mixture can be found in Jean Jacques, Andre Collet,Samuel H. Wilen, “Enantiomers, Racemates and Resolutions,” John WileyAnd Sons, Inc., 1981, herein incorporated by reference in its entirety.

Additionally, the compounds and methods provided herein may exist asgeometric isomers. The compounds and methods provided herein include allcis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well asthe appropriate mixtures thereof. In some situations, compounds mayexist as tautomers. All tautomers are included within the formulasdescribed herein are provided by compounds and methods herein. Inadditional embodiments of the compounds and methods provided herein,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion may also be useful forthe applications described herein.

Pharmaceutical Composition/Formulation/Administration

For convenience, the form and other characteristics of the compoundsdescribed in this section and other parts herein use a single formula,such as “Formula (A) or Formula (B),” by way of example. However, theform and other characteristics of the compounds described herein applyequally well to all formulas presented herein that fall within the scopeof Formula (A) or Formula (B). For example, the form and othercharacteristics of the compounds described herein can be applied tocompounds having the structure of any of Formula (1) to Formula (54), aswell as to all of the specific compounds that fall within the scope ofthese generic formulas.

A pharmaceutical composition, as used herein, refers to a mixture of atleast one compound of Formula (A) or Formula (B) with other chemicalcomponents, such as carriers, stabilizers, diluents, dispersing agents,suspending agents, thickening agents, and/or excipients. Thepharmaceutical composition facilitates administration of the compound toan organism. Pharmaceutical compositions containing compounds of Formula(A) or Formula (B) can be administered in therapeutically effectiveamounts as pharmaceutical compositions by any conventional form androute known in the art including, but not limited to: intravenous, oral,rectal, aerosol, parenteral, ophthalmic, pulmonary, transdermal,vaginal, otic, nasal, and topical administration.

One may administer the compound in a local rather than systemic manner,for example, via injection of the compound directly into an organ, oftenin a depot or sustained release formulation. Furthermore, one mayadminister pharmaceutical composition containing compounds of Formula(A) or Formula (B) in a targeted drug delivery system, for example, in aliposome coated with organ-specific antibody. The liposomes will betargeted to and taken up selectively by the organ. In addition, thepharmaceutical composition containing compounds of Formula (A) orFormula (B) may be provided in the form of a rapid release formulation,in the form of an extended release formulation, or in the form of anintermediate release formulation.

For oral administration, compounds of Formula (A) or Formula (B) can beformulated readily by combining the active compounds withpharmaceutically acceptable carriers or excipients well known in theart. Such carriers enable the compounds described herein to beformulated as tablets, powders, pills, dragees, capsules, liquids, gels,syrups, elixirs, slurries, suspensions and the like, for oral ingestionby a patient to be treated.

Pharmaceutical preparations for oral use can be obtained by mixing oneor more solid excipient with one or more of the compounds describedherein, optionally grinding the resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as: for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents may be added, such as the cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, or gels formulated in conventional manner.Parental injections may involve for bolus injection or continuousinfusion. The pharmaceutical composition of Formula (A) or Formula (B)may be in a form suitable for parenteral injection as a sterilesuspensions, solutions or emulsions in oily or aqueous vehicles, and maycontain formulatory agents such as suspending, stabilizing and/ordispersing agents. Pharmaceutical formulations for parenteraladministration include aqueous solutions of the active compounds inwater-soluble form. Additionally, suspensions of the active compoundsmay be prepared as appropriate oily injection suspensions. Suitablelipophilic solvents or vehicles include fatty oils such as sesame oil,or synthetic fatty acid esters, such as ethyl oleate or triglycerides,or liposomes. Aqueous injection suspensions may contain substances whichincrease the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may alsocontain suitable stabilizers or agents which increase the solubility ofthe compounds to allow for the preparation of highly concentratedsolutions. Alternatively, the active ingredient may be in powder formfor constitution with a suitable vehicle, e.g., sterile pyrogen-freewater, before use.

The compounds of Formula (A) or Formula (B) can be administeredtopically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical compounds can contain solubilizers, stabilizers, tonicityenhancing agents, buffers and preservatives.

Formulations suitable for transdermal administration of compounds havingthe structure of Formula (A) or Formula (B) may employ transdermaldelivery devices and transdermal delivery patches and can be lipophilicemulsions or buffered, aqueous solutions, dissolved and/or dispersed ina polymer or an adhesive. Such patches may be constructed forcontinuous, pulsatile, or on demand delivery of pharmaceutical agents.Still further, transdermal delivery of the compounds of Formula (A) orFormula (B) can be accomplished by means of iontophoretic patches andthe like. Additionally, transdermal patches can provide controlleddelivery of the compounds Formula (A) or Formula (B). The rate ofabsorption can be slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. Conversely,absorption enhancers can be used to increase absorption. An absorptionenhancer or carrier can include absorbable pharmaceutically acceptablesolvents to assist passage through the skin. For example, transdermaldevices are in the form of a bandage comprising a backing member, areservoir containing the compound optionally with carriers, optionally arate controlling barrier to deliver the compound to the skin of the hostat a controlled and predetermined rate over a prolonged period of time,and means to secure the device to the skin.

For administration by inhalation, the compounds of Formula (A) orFormula (B) may be in a form as an aerosol, a mist or a powder.Pharmaceutical compositions of Formula (A) or Formula (B) areconveniently delivered in the form of an aerosol spray presentation frompressurized packs or a nebuliser, with the use of a suitable propellant,e.g., dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof, such as, by way of example only, gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds of Formula (A) or Formula (B) may also be formulated inrectal compositions such as enemas, rectal gels, rectal foams, rectalaerosols, suppositories, jelly suppositories, or retention enemas,containing conventional suppository bases such as cocoa butter or otherglycerides, as well as synthetic polymers such as polyvinylpyrrolidone,PEG, and the like. In suppository forms of the compositions, alow-melting wax such as, but not limited to, a mixture of fatty acidglycerides, optionally in combination with cocoa butter is first melted.

In practicing the methods of treatment or use provided herein,therapeutically effective amounts of compounds of Formula (A) or Formula(B) provided herein are administered in a pharmaceutical composition toa mammal having a disease or condition to be treated. Preferably, themammal is a human. A therapeutically effective amount can vary widelydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Thecompounds can be used singly or in combination with one or moretherapeutic agents as components of mixtures.

Pharmaceutical compositions may be formulated in conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art. Pharmaceutical compositionscomprising a compound of Formula (A) or Formula (B) may be manufacturedin a conventional manner, such as, by way of example only, by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or compression processes.

The pharmaceutical compositions will include at least onepharmaceutically acceptable carrier, diluent or excipient and a compoundof Formula (A) or Formula (B) described herein as an active ingredientin free-acid or free-base form, or in a pharmaceutically acceptable saltform. In addition, the methods and pharmaceutical compositions describedherein include the use of N-oxides, crystalline forms (also known aspolymorphs), as well as active metabolites of these compounds having thesame type of activity. In some situations, compounds may exist astautomers. All tautomers are included within the scope of the compoundspresented herein. Additionally, the compounds described herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. The solvated forms of thecompounds presented herein are also considered to be disclosed herein.In addition, the pharmaceutical compositions may include other medicinalor pharmaceutical agents, carriers, adjuvants, such as preserving,stabilizing, wetting or emulsifying agents, solution promoters, saltsfor regulating the osmotic pressure, and/or buffers. In addition, thepharmaceutical compositions can also contain other therapeuticallyvaluable substances.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundas disclosed herein. Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The compositions may be inliquid solutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionsmay also contain minor amounts of nontoxic, auxiliary substances, suchas wetting or emulsifying agents, pH buffering agents, and so forth.

A summary of pharmaceutical compositions described herein may be found,for example, in Remington: The Science and Practice of Pharmacy,Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, JohnE., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton,Pa. 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999), herein incorporated by reference in their entirety.

Methods of Administration and Treatment Methods

For convenience, the form and other characteristics of the compoundsdescribed in this section and other parts herein use a single formula,such as “Formula (A) or Formula (B),” by way of example. However, theform and other characteristics of the compounds described herein applyequally well to all formulas presented herein that fall within the scopeof Formula (A) or Formula (B). For example, the form and othercharacteristics of the compounds described herein can be applied tocompounds having the structure of any of Formula (1) to Formula (54), aswell as to all of the specific compounds that fall within the scope ofthese generic formulas.

The compounds of Formula (A) or Formula (B) can be used in thepreparation of medicaments for the treatment of diseases or conditionsin which c-kit receptor activity contributes to the pathology and/orsymptomology of the disease. In addition, a method for treating any ofthe diseases or conditions described herein in a subject in need of suchtreatment, involves administration of pharmaceutical compositionscontaining at least one compound of Formula (A) or Formula (B), or apharmaceutically acceptable salt, pharmaceutically acceptable N-oxide,pharmaceutically active metabolite, pharmaceutically acceptable prodrug,or pharmaceutically acceptable solvate thereof, in therapeuticallyeffective amounts to said subject

The compositions containing the compound(s) described herein can beadministered for prophylactic and/or therapeutic treatments. Intherapeutic applications, the compositions are administered to a patientalready suffering from a disease or condition, in an amount sufficientto cure or at least partially arrest the symptoms of the disease orcondition. Amounts effective for this use will depend on the severityand course of the disease or condition, previous therapy, the patient'shealth status, weight, and response to the drugs, and the judgment ofthe treating physician. It is considered well within the skill of theart for one to determine such therapeutically effective amounts byroutine experimentation (including, but not limited to, a doseescalation clinical trial).

Compositions containing the compound(s) described herein can be used totreat a disease-state or condition selected from: neoplastic diseases,including, but not limited to, mastocytosis, canine mastocytoma, humangastrointestinal stromal tumor, small cell lung cancer, non-small celllung cancer, acute myelocytic leukemia, acute lymphocytic leukemia,myelodysplastic syndrome, chronic myelogenous leukemia, colorectalcarcinomas, gastric carcinomas, gastrointestinal stromal tumors,testicular cancers, glioblastomas, and astrocytomas; allergic diseases,including, but not limited to, asthma, allergic rhinitis, allergicsinusitis, anaphylactic syndrome, urticaria, angioedema, atopicdermatitis, allergic contact dermatitis, erythema nodosum, erythemamultiforme, cutaneous necrotizing venulitis and insect bite skininflammation and blood sucking parasitic infestation; inflammatorydiseases including, but not limited to, rheumatoid arthritis,conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritisand other arthritic conditions; autoimmune diseases, including, but notlimited to, multiple sclerosis, psoriasis, intestine inflammatorydisease, ulcerative colitis, Crohn's disease, rheumatoid arthritis andpolyarthritis, local and systemic scleroderma, systemic lupuserythematosus, discoid lupus erythematosus, cutaneous lupus,dermatomyositis, polymyositis, Sjogren's syndrome, nodular panarteritis,autoimmune enteropathy, and proliferative glomerulonephritis;graft-versus-host disease, including, but not limited to, organtransplantation graft rejection, such as, but not limited to, kidneytransplantation, pancreas transplantation, liver transplantation, hearttransplantation, lung transplantation, or bone marrow transplantation;metabolic syndrome, including, but not limited to, type I diabetes, typeII diabetes, or obesity; CNS related disorders, including, but notlimited to, depression, dysthymic disorder, cyclothymic disorder,bipolar depression, severe or “melancholic” depression, atypicaldepression, refractory depression, seasonal depression, anorexia,bulimia, premenstrual syndrome and post-menopause syndrome, as mentalslowing and loss of concentration, pessimistic worry, agitation,self-deprecation and decreased libido, as anxiety disorders includinganxiety associated with hyperventilation and cardiac arrhythmias, phobicdisorders, obsessive-compulsive disorder, posttraumatic stress disorder,acute stress disorder, and generalized anxiety disorder, as psychiatricdisorders such as panic attacks, including psychosis, delusionaldisorders, conversion disorders, phobias, mania, delirium, dissociativeepisodes including dissociative amnesia, dissociative fugue anddissociative suicidal behavior, self-neglect, violent or aggressivebehavior, trauma, borderline personality, and acute psychosis asschizophrenia including paranoid schizophrenia, disorganizedschizophrenia, catatonic schizophrenia, and undifferentiatedschizophrenia; neurodegenerative disease, including, but not limited to,Alzheimer's disease, Parkinson's disease, Huntington's disease, theprion diseases, Motor Neuron Disease (MND), and Amyotrophic LateralSclerosis (ALS); pain, including, but not limited to, acute pain,postoperative pain, chronic pain, nociceptive pain, cancer pain,neuropathic pain, and psychogenic pain syndromes; substance usedisorders, including, but not limited to, drug addiction, drug abuse,drug habituation, drug dependence, withdrawal syndrome and overdose,prion diseases, cancers, heart diseases, fibrotic diseases, idiopathicpulmonary arterial hypertension (IPAH), and primary pulmonaryhypertension (PPH); in a patient in need of such treatment, the methodcomprising administering to the patient an effective amount of acompound described herein, or a tautomer, prodrug, solvate, or saltthereof.

In the case wherein the patient's condition does not improve, upon thedoctor's discretion the administration of the compounds may beadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition. In the case wherein the patient's status doesimprove, upon the doctor's discretion the administration of thecompounds may be given continuously or temporarily suspended for acertain length of time (i.e., a “drug holiday”).

Once improvement of the patient's conditions has occurred, a maintenancedose is administered if necessary. Subsequently, the dosage or thefrequency of administration, or both, can be reduced, as a function ofthe symptoms, to a level at which the improved disease or condition isretained. Patients can, however, require intermittent treatment on along-term basis upon any recurrence of symptoms.

In certain instances, it may be appropriate to administertherapeutically effective amounts of at least one of the compoundsdescribed herein (or a pharmaceutically acceptable salts,pharmaceutically acceptable N-oxides, pharmaceutically activemetabolites, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable solvates thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is inflammation,then it may be appropriate to administer an anti-inflammatory agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. In any case, regardless of the disease or condition beingtreated, the overall benefit experienced by the patient may simply beadditive of the two therapeutic agents or the patient may experience asynergistic benefit. For example, synergistic effects can occur withcompounds of Formula (A) or Formula (B) and other substances used in thetreatment of neoplastic disease, allergy disease, inflammatory disease,autoimmume disease, graft-versus-host disease, metabolic syndrome, CNSrelated disorders, neurodegenerative disease, pain, substance abusedisorders, prion diseases, cancers, heart diseases, fibrotic diseases,idiopathic pulmonary arterial hypertension (IPAH), or primary pulmonaryhypertension (PPH). Examples of such bronchodilators, including, but notlimited to, β₂-agonists, methylxanthines and anticholinerigcs;anti-inflammatory agents, including, but not limited to, corticosteroidsand cromolyns, leukotriene antagonists, and IgE blockers, including butnot limited to, omalizumab, also known as xolair. Where the compoundsdescribed herein are administered in conjunction with other therapies,dosages of the co-administered compounds will of course vary dependingon the type of co-drug employed, on the specific drug employed, on thedisease or condition being treated and so forth. In addition, whenco-administered with one or more biologically active agents, thecompound provided herein may be administered either simultaneously withthe biologically active agent(s), or sequentially. If administeredsequentially, the attending physician will decide on the appropriatesequence of administering protein in combination with the biologicallyactive agent(s).

In any case, the multiple therapeutic agents (one of which is one of thecompounds described herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may vary from more than zero weeks to less than fourweeks. In addition, the combination methods, compositions andformulations are not to be limited to the use of only two agents; weenvision the use of multiple therapeutic combinations.

In addition, the compounds of Formula (A) or Formula (B) may also beused in combination with procedures that may provide additional orsynergistic benefit to the patient. By way of example only, patients areexpected to find therapeutic and/or prophylactic benefit in the methodsdescribed herein, wherein pharmaceutical composition of Formula (A) orFormula (B) and/or combinations with other therapeutics are combinedwith genetic testing to determine whether that individual is a carrierof a mutant gene that is known to be correlated with certain diseases orconditions.

The compounds of Formula (A) or Formula (B) and combination therapiescan be administered before, during or after the occurrence of a diseaseor condition, and the timing of administering the composition containinga compound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to conditions or diseases in order to prevent the occurrenceof the disease or condition. The compounds and compositions can beadministered to a subject during or as soon as possible after the onsetof the symptoms. The administration of the compounds can be initiatedwithin the first 48 hours of the onset of the symptoms, preferablywithin the first 48 hours of the onset of the symptoms, more preferablywithin the first 6 hours of the onset of the symptoms, and mostpreferably within 3 hours of the onset of the symptoms. The initialadministration can be via any route practical, such as, for example, anintravenous injection, a bolus injection, infusion over 5 minutes toabout 5 hours, a pill, a capsule, transdermal patch, buccal delivery,and the like, or combination thereof. A compound is preferablyadministered as soon as is practicable after the onset of a disease orcondition is detected or suspected, and for a length of time necessaryfor the treatment of the disease, such as, for example, from about 1month to about 3 months. The length of treatment can vary for eachsubject, and the length can be determined using the known criteria. Forexample, the compound or a formulation containing the compound can beadministered for at least 2 weeks, preferably about 1 month to about 5years, and more preferably from about 1 month to about 3 years.

The pharmaceutical composition described herein may be in unit dosageforms suitable for single administration of precise dosages. In unitdosage form, the formulation is divided into unit doses containingappropriate quantities of one or more compound. The unit dosage may bein the form of a package containing discrete quantities of theformulation. Non-limiting examples are packaged tablets or capsules, andpowders in vials or ampoules. Aqueous suspension compositions can bepackaged in single-dose non-reclosable containers. Alternatively,multiple-dose reclosable containers can be used, in which case it istypical to include a preservative in the composition. By way of exampleonly, formulations for parenteral injection may be presented in unitdosage form, which include, but are not limited to ampoules, or inmulti-dose containers, with an added preservative.

The daily dosages appropriate for the compounds of Formula (A) orFormula (B) described herein are from about 0.03 to 2.5 mg/kg per bodyweight. An indicated daily dosage in the larger mammal, including, butnot limited to, humans, is in the range from about 0.5 mg to about 100mg, conveniently administered in divided doses, including, but notlimited to, up to four times a day or in retard form. Suitable unitdosage forms for oral administration comprise from about 1 to 50 mgactive ingredient. The foregoing ranges are merely suggestive, as thenumber of variables in regard to an individual treatment regime islarge, and considerable excursions from these recommended values are notuncommon. Such dosages may be altered depending on a number ofvariables, not limited to the activity of the compound used, the diseaseor condition to be treated, the mode of administration, the requirementsof the individual subject, the severity of the disease or conditionbeing treated, and the judgment of the practitioner.

Toxicity and therapeutic efficacy of such therapeutic regimens can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, for determining theLD₅₀ (the dose lethal to 50% of the population) and the ED₅₀ (the dosetherapeutically effective in 50% of the population). The dose ratiobetween the toxic and therapeutic effects is the therapeutic index andit can be expressed as the ratio between LD₅₀ and ED₅₀. Compoundsexhibiting high therapeutic indices are preferred. The data obtainedfrom cell culture assays and animal studies can be used in formulating arange of dosage for use in human. The dosage of such compounds liespreferably within a range of circulating concentrations that include theED₅₀ with minimal toxicity. The dosage may vary within this rangedepending upon the dosage form employed and the route of administrationutilized.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also described herein. Such kits cancomprise a carrier, package, or container that is compartmentalized toreceive one or more containers such as vials, tubes, and the like, eachof the container(s) comprising one of the separate elements to be usedin a method described herein. Suitable containers include, for example,bottles, vials, syringes, and test tubes. The containers can be formedfrom a variety of materials such as glass or plastic.

For example, the container(s) can comprise one or more compoundsdescribed herein, optionally in a composition or in combination withanother agent as disclosed herein. The container(s) optionally have asterile access port (for example the container can be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). Such kits optionally comprising a compound with anidentifying description or label or instructions relating to its use inthe methods described herein.

A kit will typically may comprise one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

ILLUSTRATIVE EXAMPLES

The following examples provide illustrative methods for making andtesting the effectiveness and safety of the compounds of Formula (A) orFormula (B). These examples are provided for illustrative purposes onlyand not to limit the scope of the claims provided herein. All of themethods disclosed and claimed herein can be made and executed withoutundue experimentation in light of the present disclosure. It will beapparent to those of skill in the art that variations may be applied tothe methods and in the steps or in the sequence of steps of the methoddescribed herein without departing from the concept, spirit and scope ofthe claims. All such similar substitutes and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the appended claims.

Example 1 Synthesis of Substituted Nitro-Benzene Compounds Example 1aDiethyl-[2-(4-nitro-phenoxy)-ethyl]-amine

Diethyl-[2-(4-nitro-phenoxy)-ethyl]-amine can be synthesized by thefollowing procedure. To a solution of 4-nitro-phenol (36.0 mmol) intoluene (40 mL) is added cesium carbonate (53.8 mmol) followed by(2-chloro-ethyl)-diethyl-amine hydrochloride (28.7 mmol) and thereaction mixture is heated at 100° C. for 2 h. The reaction mixture iscooled down and the solid is filtered under vacuum and washed with warmtoluene. The filtrate is concentrated to afford 3.35 g ofdiethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (39%) that is used in the nextstep without further purification. ¹HNMR (400 MHz, CDCl₃) δ 8.10-8.08(m, 2H), 6.86-6.84 (m, 2H), 4.05 (t, J=4.0 Hz, 2H), 2.81 (t, J=4.0 Hz),2.55 (q, J=8.0 Hz, 4H), 0.98 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 230.3.

Example 1b Diethyl-[2-(4-nitro-phenylsulfanyl)-ethyl]-amine

Diethyl-[2-(4-nitro-phenylsulfanyl)-ethyl]-amine can be synthesized bythe following procedure. To a solution of 4-nitro-thiophenol (3.6.0mmol) in toluene (40 mL) is added cesium carbonate (53.8 mmol) followedby (2-chloro-ethyl)-diethyl-amine hydrochloride (28.7 mmol). Thereaction mixture is heated at 100° C. for 2 h. The reaction mixture iscooled down and the solid is filtered under vacuum and washed with warmtoluene. The filtrate is concentrated to afforddiethyl-[2-(4-nitro-phenylsulfanyl)-ethyl]-amine that is used in thenext step without further purification. ¹HNMR (400 MHz, CDCl₃) δ8.23-8.11 (m, 2H), 7.35-7.33 (m, 2H), 3.13 (t, J=8.0 Hz, 2H), 2.77 (t,J=8.0 Hz, 2H), 2.60 (q, J=8.0 Hz, 4H), 1.05 (t, J=8.0 Hz, 6H). MS (m/z)(M+1)⁺ 255.2.

Example 1c 1-(2-Chloro-ethoxy)-4-nitro-benzene

1-(2-Chloro-ethoxy)-4-nitro-benzene can be synthesized by the followingprocedure. To a solution of 4-nitro-phenol (28.7 mmol) in absoluteethanol (15 mL) is added cesium carbonate (28.7 mmol) followed by1-bromo-2-chloro-ethane (86.2 mmol). The reaction mixture is heated at80° C. for 8 h. The reaction mixture is cooled down and quenched withwater and extracted with EtOAc. The organic layer is washed with water,brine, dried over Na₂SO₄, and concentrated to afford an orange residuethat upon trituration with EtOH gives1-(2-chloro-ethoxy)-4-nitro-benzene (66%). MS (m/z) (M+1)⁺ 202.2.

Example 1d 4-[2-(4-Nitro-phenyl)-ethyl]-morpholine

4-[2-(4-Nitro-phenyl)-ethyl]-morpholine can be synthesized by thefollowing procedure. A solution of 1-(2-bromo-ethyl)-4-nitro-benzene(8.7 mmol) in anhydrous DMF (15 mL) and morpholine (17.3 mmol) is heatedat 80° C. under a nitrogen atmosphere for 8 h. The reaction mixture iscooled down and quenched with water and extracted with EtOAc. Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated to afford 4-[2-(4-nitro-phenyl)-ethyl]-morpholine (93%) asa yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 8.15-8.13 (m, 2H), 7.38-7.36 (m,2H), 6.86-6.84 (m, 2H), 3.75 (m, 4H), 2.91 (t, J=8.0 Hz, 2H), 2.65 (t,J=8.0 Hz, 4H), 2.55 (m, 4H). MS (m/z) (M+1)⁺ 237.2.

Example 1e 3-Nitrophenyl 4-methylpiperazine-1-carboxylate

3-Nitrophenyl 4-methylpiperazine-1-carboxylate can be synthesized by thefollowing procedure. A dry flask containing 3-nitro-phenol (28 mmol) andtriphosgene (18.7 mmol) in 100 mL dichloromethane is cooled in anice-water bath. Diisopropylethylamine (28 mmol) is slowly added. Thereaction is stirred at rt for 2 h and then refluxed for another 2 h. Themixture is concentrated to dryness. The residue is dissolved in 100 mLof THF and triethylamine (40 mmol) and N-methylpiperazine (30 mmol) areadded. The mixture is stirred overnight and concentrated. The residue isdissolved in dichloromethane and washed with 10% NaHCO₃. The organiclayer is separated, dried over sodium sulfate, and concentrated. Thecrude product is used in the next step without further purification.

Example 1f 4-Nitrophenyl 4-methylpiperazine-1-carboxylate

4-Nitrophenyl 4-methylpiperazine-1-carboxylate can be synthesized by thefollowing procedure. A dry flask containing 4-nitro-phenol (28 mmol) andtriphosgene (18.7 mmol) in 100 mL dichloromethane is cooled in anice-water bath. Diisopropylethylamine (28 mmol) is slowly added. Thereaction is stirred at rt for 2 h and then refluxed for another 2 h. Themixture is concentrated to dryness. The residue is dissolved in 100 mLof THF and triethylamine (40 mmol) and N-methylpiperazine (30 mmol) areadded. The mixture is stirred overnight and concentrated. The residue isdissolved in dichloromethane and washed with 10% NaHCO₃. The organiclayer is separated, dried over sodium sulfate, and concentrated. Thecrude product is used in the next step without further purification.

Examples 1g Diethyl-[2-(3-nitro-phenoxy)-ethyl]-amine

Diethyl-[2-(3-nitro-phenoxy)-ethyl]-amine can be synthesize by thefollowing procedure. To a solution of 3-nitro-phenol (7.2 mmol) inanhydrous EtOH (20 mL), cesium carbonate (10.8 mmol) is added followedby (2-chloro-ethyl)-diethyl-amine hydrochloride (7.0 mmol) and thereaction mixture is refluxed for 12 h. The reaction mixture is cooleddown and the solid filtered under vacuum and washed with warm EtOH. Thefiltrate is concentrated, dissolved in DCM (50 mL), washed with water,brine, dried over Na₂SO₄, and concentrated to afford 1.45 g of the titlecompound (84%) that is used without further purification. ¹HNMR (400MHz, CDCl₃) δ 7.82-8.80 (m, 1H), 7.74-7.73 (m, 1H), 7.43-7.38 (m, 1H),7.23-7.21 (m, 1H), 4.12 (dt, J=8.0 and 4.0 Hz, 2H), 2.91 (dt. J=8.0 and4.0 Hz, 2H), 2.69-2.63 (m, 4H), 1.11-1.06 (m, 6H). MS (m/z) (M+1)⁺239.2.

Examples 1h 2-Hydroxy-4-nitro-benzoic acid methyl ester

2-Hydroxy-4-nitro-benzoic acid methyl ester can be synthesized by thefollowing procedure. To a suspension of 2-hydroxy-4-nitro-benzoic acid(5.4 mmol) in anhydrous ACN (20 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene(5.4 mmol) is added drop wise followed by methyl iodide (5.4 mmol). Thereaction is stirred at rt for 1 h. The solvent is removed under reducedpressure and the yellow residue is dissolved in DCM (50 mL) washed with2N HCl (2×20 mL), 5% Na₂CO₃ (2×30 mL), brine, dried over Na₂SO₄ andconcentrated to afford 2-hydroxy-4-nitro-benzoic acid methyl ester as apale yellow solid (84%). MS (m/z) (M+1)⁺ 198.1.

Example 1i2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester

2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester can be prepared by the following procedure. To asolution of 2-hydroxy-4-nitro-benzoic acid methyl ester (2.5 mmol) inDMF (10 mL), is added cesium carbonate (3.5 mmol) followed by(2-chloro-ethyl)-diethyl-amine hydrochloride (3.5 mmol). The reactionmixture is heated at 80° C. for 8 h. After this time the reaction iscooled down, diluted with water (50 mL) and extracted with EtOAc (3×30mL). The combined organic layer is washed with water (2×20 mL), brine,dried over Na₂SO₄ and concentrated to afford2-(2-diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester (69%) as a yellow oil that is used without furtherpurification. ¹HNMR (400 MHz, DMSO) δ 7.48 (d, J=8 Hz, 1H), 6.20-6.19(m, 1H), 6.14-6.12 (m, 1H), 5.88 (bs, 2H), 3.92 (t, J=8.0 Hz, 2H), 3.64(s, 3H), 2.77 (t. J=8.0 Hz, 2H), 2.56 (q, J=8.0 Hz, 4H), 10.97 (t, J=8.0Hz, 6H). MS (m/z) (M+1)⁺ 267.2.

Example 1j 3-Nitrophenethyl methanesulfonate

3-Nitrophenethyl methanesulfonate can be synthesized by the followingprocedure. To a solution of 2-(3-nitrophenyl)ethanol (17.9 mmol) andtriethylamine (23.3 mmol) in DCM (50 mL), is added methanesulfonylchloride (18.8 mmol) in DCM (10 mL) at 0° C. under a nitrogenatmosphere. After the addition is complete, the reaction is allowed towarm to rt and it is stirred for another 2 h. The solvent is removed andthe residue is dissolved in DCM (100 mL). The organic layer is washedwith water, dried over Na₂SO₄ and concentrated to afford3-nitrophenethyl methanesulfonate (98%) that is used without furtherpurification. MS (m/z) (M+1)⁺ 246.2.

Example 1k N,N-Diethyl-2-(3-nitrophenyl)ethanamine

N,N-diethyl-2-(3-nitrophenyl)ethanamine can be prepared by the followingprocedure. A mixture of diethyl amine (9.0 mmol) and K₂CO₃ (9.9 mmol) inACN (50 mL) is refluxed for 1 h under nitrogen atmosphere. To the abovemixture, a solution of 3-nitrophenethyl methanesulfonate (8.2 mmol) inACN (10 mL) is added and the mixture is refluxed for 1 h. The solvent isremoved and the residue is dissolved in DCM (100 mL). The organic layeris washed with water, dried over Na₂SO₄ and concentrated to afford aresidue which is purified by silica gel column chromatography(EtOAc:hexane=30:70) to afford N,N-diethyl-2-(3-nitrophenyl)ethanamine(75%). ¹HNMR (400 MHz, CDCl₃) δ 8.04-8.10 (m, 2H), 7.51-7.55 (d, J=7.6Hz, 1H), 7.43 (t, J=7.8 Hz, 1H), 2.81-2.88 (m, 2H), 2.67-2.74 (m, 2H),2.59 (q, J=7.2 Hz, 4H), 1.04 (t. J=7.2 Hz, 6H). MS (m/z) (M+1)⁺ 223.2.

Example 1l 3-nitrobenzyl 4-methylpiperazine-1-carboxylate

3-nitrobenzyl 4-methylpiperazine-1-carboxylate can be synthesized by thefollowing procedure. To a suspension of NaH (60% weight in mineral oil,12.0 mmol) in THF (20 mL), is added (3-nitrophenyl)methanol (8.0 mmol)slowly. The reaction mixture is stirred at rt for 5 min. A solution of4-methylpiperazine-1-carbonyl chloride (10.0 mmol) in THF (5 mL) isadded to the above reaction mixture and stirred for 3 h. Upon reactioncompletion, H₂O (1 mL) is added to quench the reaction. The solvent isremoved and the residue is dissolved in EtOAc (100 mL). The organiclayer is washed with water, dried over Na₂SO₄ and concentrated to afforda residue which is purified by silica gel column chromatography(EtOAc:hexane=30:70) to afford 3-nitrobenzyl4-methylpiperazine-1-carboxylate (80%). ¹HNMR (400 MHz, CDCl₃) δ 8.20(s, 1H), 8.15 (d, J=7.8 Hz, 1H), 7.67 (d, J=7.8 Hz, 1H), 7.53 (t, J=7.8Hz, 1H), 5.20 (s, 2H), 3.50-3.55 (m, 4H), 2.29 (s, 3H). MS (m/z) (M+1)⁺280.2.

Example 1m 2-(methoxycarbonyl)-5-nitrophenyl4-methylpiperazine-1-carboxylate

To a dry flask are added 2-hydroxy-4-nitro-benzoic acid methyl ester (40mmol) (from Example 1h) and triphosgene (26.6 mmol) and DCM (100 mL).The reaction mixture is cooled to 0° C. and diisopropylethylamine (40mmol) is added slowly. After addition the mixture is warmed to rt. After1 h at this temperature it is refluxed for 1 h. The mixture is cooleddown and the solvents are removed. THF (100 mL), Et₃N (80 mmol), andN-methyl piperazine (80 mmol) are added and the mixture is stirred at rtovernight. The solvent is removed and the residue dissolved in EtOAc.Phases are separated upon addition of a 10% solution of NaHCO₃. Theorganic phase is washed with brine, dried on Na₂SO₄ and evaporated. Thecrude is used in the following reaction.

Example 1n 2-(2-Diethylamino-ethoxy)-5-nitro-benzoic acid ethyl ester

2-(2-Diethylamino-ethoxy)-5-nitro-benzoic acid ethyl ester can besynthesized by the following procedure. A solution of methyl5-nitrosalicylate (7.61 mmol) in anhydrous EtOH (20 mL) is treated withCs₂CO₃ (11.4 mmol) and (2-chloro-ethyl)-diethyl-amine hydrochloride(7.61 mmol). The reaction mixture is stirred at 80° C. for 4 h, then thesolvent is removed and the thick oil residue is purified by HPLC (ACNgradient 10-90%) to afford the title compounds (25%). ¹HNMR (400 MHz,DMSO) δ 9.58 (b.s. 1H), 8.53-8.54 (m, 1H), 8.50-8.47 (m, 1H), 4.58-4.57(m, 2H), 4.31 (q, J=8.0 Hz, 2H), 3.61-3.60 (m, 2H), 3.32-3.27 (m, 4H),1.33 (t, J=8.0 Hz, 3H), 1.24 (t, J=8.0 Hz, 6H); MS (m/z) (M+1)⁺ 311.1.

Example 2 Synthesis of Substituted Aniline Compounds Example 2a4-(2-Diethylamino-ethoxy)-phenylamine

4-(2-Diethylamino-ethoxy)-phenylamine can be synthesized by thefollowing procedure. To a solution ofdiethyl-[2-(4-nitro-phenoxy)-ethyl]-amine (14.0 mmol) (from Example 1a)in MeOH (20 mL), in a Parr pressure bottle, is added Pd (10% on carbon,50% wet, 10% weight). The suspension is shaken at 50 psi of H2 for 2 h.The reaction mixture is filtered through celite. The solvent is removedand the residue is dissolved in MeOH (20 mL) and treated with HCl (1 eqof a 4N solution in dioxane) to afford the4-(2-diethylamino-ethoxy)-phenylamine as hydrochloride salt (99%). ¹HNMR(400 MHz, DMSO) δ 6.98-6.91 (m, 4H), 4.30 (t, J=4.0 Hz, 2H), 3.47 (t,J=4.0 Hz), 3.20 (m, 4H), 1.24 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 209.3.

Example 2b 4-(2-Diethylamino-ethylsulfanyl)-phenylamine

4-(2-Diethylamino-ethylsulfanyl)-phenylamine can be synthesized by thefollowing procedure. A suspension ofdiethyl-[2-(4-nitro-phenylsulfanyl)-ethyl]-amine (3.9 mmol) (fromExample 1b) and SnCl₂ 2H₂O (15.7 mmol) in absolute ethanol (30 mL) isheated at 70° C. for 2 h. The solvent is removed under vacuum and theresidue is dissolved in 5% NaOH and extracted with EtOAc (3×50 mL). Theorganic layer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine,dried over Na₂SO₄ and concentrated to afford4-(2-diethylamino-ethylsulfanyl)-phenylamine (91%). ¹HNMR (400 MHz,CDCl₃) δ 8.23-8.11 (m, 2H), 7.35-7.33 (m, 2H), 3.13 (t, J=8.0 Hz, 2H),2.77 (t, J=8.0 Hz, 2H), 2.60 (q, J=8.0 Hz, 4H), 1.05 (t, J=8.0 Hz, 6H).MS (m/z) (M+1)⁺ 255.2.

Example 2c 4-(2-Chloro-ethoxy)-phenylamine

4-(2-Chloro-ethoxy)-phenylamine can be synthesized by the followingprocedure. A suspension of 1-(2-chloro-ethoxy)-4-nitro-benzene (1.5mmol) (from Example 1c) and SnCl₂.2H₂O (5.9 mmol) in absolute ethanol(120 mL) is heated at 70° C. for 2 h. The solvent is removed undervacuum and the residue is dissolved in 5% NaOH and extracted with EtOAc(3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water(1×50 mL), brine, and dried over Na₂SO₄ and reduced to dryness. The darkcrude residue is purified by silica chromatography using a mixture ofDCM:MeOH:NH₄OH=9:1:0.1 to isolate 4-(2-chloro-ethoxy)-phenylamine (90%)which is converted in the hydrochloride salt by treatment with HCl (1 eqof a 4N solution in dioxane). ¹HNMR (400 MHz, CD₃OD) δ 7.35-7.33 (m,2H), 7.16-7.05 (m, 2H), 4.38 (m, 2H), 3.87 (m, 2H). MS (m/z) (M+1)⁺173.1.

Example 2d 4-(2-Morpholin-4-yl-ethyl)-phenylamine

4-(2-Morpholin-4-yl-ethyl)-phenylamine can be synthesized by thefollowing procedure. To a solution of4-[2-(4-nitro-phenyl)-ethyl]-morpholine (14.0 mmol) (from Example 1d) inMeOH (20 mL), in a Parr pressure bottle, is added Pd (10% on carbon, 50%wet, 10% weight). The reaction mixture is shaken at 50 psi of H₂ for 2h. The reaction mixture is filtered through celite. The solvent isremoved to afford 4-(2-morpholin-4-yl-ethyl)-phenylamine. MS (m/z)(M+1)⁺ 207.2.

Example 2e 3-Aminophenyl 4-methylpiperazine-1-carboxylate

3-Aminophenyl 4-methylpiperazine-1-carboxylate can be synthesized withthe following procedure. The crude 3-nitrophenyl4-methylpiperazine-1-carboxylate (28 mmol) (from Example 1e) isdissolved in MeOH (100 mL) and added Pd (5% on carbon, 50% wet, 10%weight). The flask is charged with a hydrogen balloon and stirredovernight. The mixture is filtered through celite. The filtrate isconcentrated and further purified by silica gel column chromatography(DCM:MeOH=30:70) to afford 3-aminophenyl4-methylpiperazine-1-carboxylate (81%). ¹HNMR (400 MHz, CDCl₃) δ 7.11(m, 1H), 6.52-6.47 (m, 2H), 6.44 (s, 1H), 3.71 (br, 4H), 3.63 (br, 2H),2.52 (br, 4H), 2.38 (s, 3H). MS (m/z) (M+1)⁺ 236.1.

Example 2f 4-aminophenyl 4-methylpiperazine-1-carboxylate

4-Aminophenyl 4-methylpiperazine-1-carboxylate can be synthesized withthe following procedure. The crude 4-nitrophenyl4-methylpiperazine-1-carboxylate (28 mmol) (from Example 1f) isdissolved in MeOH (100 mL) followed by addition of Pd (5% on carbon, 50%wet, 10% weight) The flask is charged with a hydrogen balloon forovernight stirring. The mixture is filtered through celite. The filtrateis concentrated and purified by silica gel column chromatography(DCM:MeOH=30:70) to afford the 4-methyl-piperazine-1-carboxylic acid4-amino-phenyl ester (80%). ¹HNMR (400 MHz, CDCl₃) δ 6.88 (d, J=7.8 Hz,2H), 6.55 (d, J=7.8 Hz, 2H), 3.73 (br, 2H), 3.63 (br, 4H), 2.53 (br,4H), 2.40 (s, 3H). MS (m/z) (M+1)⁺ 236.1.

Example 2g 3-(2-Diethylamino-ethoxy)-phenylamine

3-(2-Diethylamino-ethoxy)-phenylamine can be prepared by the followingprocedure. To a solution of diethyl-[2-(3-nitro-phenoxy)-ethyl]-amine(2.72 mmol) (from Example 1g) in EtOH (20 mL) is added SnCl₂.2H₂O (10.9mmol). The suspension is refluxed for 2 h. After this time the solventis removed under reduced pressure. The residue is dissolved in 5% NaOH(50 mL) and extracted with EtOAc (3×50 mL). The organic layer is washedonce with 5% NaOH (20 mL), brine, dried over Na₂SO₄ and concentrated toafford the aniline as a brown oil (80%). MS (m/z) (M+1)⁺ 209.1.

Example 2h 4-Amino-2-(2-diethylamino-ethoxy)-benzoic acid methyl ester

3-(2-Diethylamino-ethoxy)-phenyl-amine can be prepared by the followingprocedure. In a Parr pressure bottle, a solution ofdiethyl-[2-(3-nitro-phenoxy)-ethyl]-amine (2.72 mmol) (from Example 1i)in MeOH (10 mL) is added Pd (5% on carbon, 50% wet, 10% weight). Thesuspension is shaken at 40 psi of H2 for 2 h. The reaction is filteredthrough celite. The solvent is removed under reduced pressure to affordthe title compound in quantitative yield. MS (m/z) (M+1)⁺ 267.1.

Example 2i 3-(2-(diethylamino)ethyl)benzenamine

3-(2-(Diethylamino)ethyl)benzenamine can be synthesized by the followingprocedure. To a solution of N,N-diethyl-2-(3-nitrophenyl)ethanamine(12.2 mmol) (from Example 1k) in MeOH (40 mL) is added Pd (5% on carbon,50% wet, 10% weight). The suspension is stirred under a balloon of H₂for 2 h. The reaction is filtered through celite. The solvent is removedunder reduced pressure to afford the title compound in quantitativeyield. ¹HNMR (400 MHz, CDCl₃) δ 7.04-7.09 (m, 1H), 6.58-6.61 (m, 1H),6.50-6.54 (m, 2H), 3.62 (br, 2H), 2.65-2.70 (m, 4H), 2.61 (q, J=7.2 Hz,4H), 1.07 (t. J=7.2 Hz, 6H). MS (m/z) (M+1)⁺ 192.2.

Example 2j 3-aminobenzyl 4-methylpiperazine-1-carboxylate

3-Aminobenzyl 4-methylpiperazine-1-carboxylate can be prepared by thefollowing procedure. A suspension of 3-nitrobenzyl4-methylpiperazine-1-carboxylate (1.5 mmol) (from Example 1l) andSnCl₂.2H₂O (5.9 mmol) in absolute ethanol (120 mL) is heated at 80° C.for 2 h. The solvent is removed under vacuum and the residue isdissolved in 5% NaOH and extracted with EtOAc (3×50 mL). The organiclayer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine, anddried over Na₂SO₄. The dark crude residue is purified by silicachromatography (DCM:MeOH=70:30) to afford 3-aminobenzyl4-methylpiperazine-1-carboxylate (90%). ¹HNMR (400 MHz, CDCl₃) δ 7.13(t, J=7.7 Hz, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (m, 1H), 6.61-6.65 (m,1H), 5.03 (s, 2H), 3.70 (br, 2H), 3.52 (t, J=5.0 Hz, 4H), 2.32-2.44 (m,4H), 2.30 (s, 3H). MS (m/z) (M+1)⁺ 250.2.

Example 2l 2-(Methoxycarbonyl)-5-aminophenyl4-methylpiperazine-1-carboxylate

2-(Methoxycarbonyl)-5-aminophenyl 4-methylpiperazine-1-carboxylate canbe prepared by the following procedure. The crude2-(methoxycarbonyl)-5-nitrophenyl 4-methylpiperazine-1-carboxylate (30mmol) (From Example 1m) is dissolved in MeOH (100 mL) followed byaddition of Pd (5% on carbon, 50% wet, 10% weight). The flask is chargedwith a hydrogen balloon for overnight stirring. The mixture is filteredover celite. The filtrate is concentrated and further purified by silicagel column chromatography (DCM:MeOH=30:70) to afford2-(methoxycarbonyl)-5-aminophenyl 4-methylpiperazine-1-carboxylate.

Example 2m 5-Amino-2-(2-diethylamino-ethoxy)-benzoic acid ethyl ester

5-Amino-2-(2-diethylamino-ethoxy)-benzoic acid ethyl ester can besynthesized by the following procedure. To2-(2-Diethylamino-ethoxy)-5-nitro-benzoic acid ethyl ester (1.6 mmol)(from Example 1n) in MeOH (12 mL) in a Parr pressure bottle is added Pd(5% on carbon, 50% wet, 10% weight). The suspension is shaken at 40 psiof H₂ for 2 h. The reaction is filtered through celite. The solvent isremoved under reduced pressure to afford the title compound inquantitative yield. MS (m/z) (M+1)⁺ 281.1.

Example 2n 6-Amino-3H-benzooxazol-2-one

6-Amino-3H-benzooxazol-2-one can be synthesized by the followingprocedure. A solution of 6-nitro-3H-benzooxazol-2-one (7.22 mmol) in a1:3 mixture EtOH:MeOH (24 mL) is treated with Pd (5% on carbon, 50% wet,10% weight). The flask is charged with a hydrogen balloon and stirredovernight. The mixture is filtered over celite and the filtrate isconcentrated to afford the 6-amino-benzoxazole-2-one as light brownpowder (95%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.06 (b.s, 1H), 6.74 (d, J=8.2Hz, 1H), 6.49 (d, J=2.0 Hz, 1H), 6.35 (dd, J=2.1 and 8.3 Hz, 1H), 4.96(s, 2H). MS (m/z) (M+1)⁺ 151.1.

Example 3 Synthesis of 5-bromo-2-aminopyrimidine compounds Example 3a(5-Bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine

(5-Bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine can besynthesized by the following procedure. A dry flask charged with4-(2-diethylamino-ethoxy)-phenylamine (6.1 mmol) (from Example 2a),p-TSA (6.1 mmol), 2-chloro-5-bromo-pyrimidine (6.1 mmol) in NMP (5 mL)is heated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (5×70 mL). Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated. Purification by silica chromatography (DCM:MeOHNH₄OH=95:5:0.1) affords5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine (50%).¹HNMR (400 MHz, CDCl₃) δ 8.37 (s, 2H), 7.43-7.40 (m, 2H), 7.02 (s, 1H),6.91-6.89 (m, 2H), 4.06 (t, J=4.0 Hz, 2H), 2.90 (t, J=4.0 Hz, 2H), 2.67(q, J=8.0 Hz, 4H), 1.09 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 366.1.

Example 3b(5-Bromo-pyridin-2-yl)-[4-(2-diethylamino-ethylsulfanyl)-phenyl]-amine

(5-Bromo-pyridin-2-yl)-[4-(2-diethylamino-ethylsulfanyl)-phenyl]-aminecan be synthesized by the following procedure. A dry flask charged with4-(2-diethylamino-ethylsulfanyl)-phenylamine (6.1 mmol) (from Example2b), p-TSA (6.1 mmol), 2-chloro-5-bromo-pyrimidine (6.1 mmol) in NMP (5mL) is heated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (5×70 mL). Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated. Purification by silica chromatography(DCM:MeOH:NH₄OH=95:5:0.1) affords(5-bromo-pyridin-2-yl)-[4-(2-diethylamino-ethylsulfanyl)-phenyl]-amine.MS (m/z) (M+1)⁺ 282.1.

Example 3c 5-Bromo-pyrimidin-2-yl)-[4-(2-chloro-ethoxy]-phenyl-amine

5-Bromo-pyrimidin-2-yl)-[4-(2-chloro-ethoxy)-phenyl-amine can besynthesized by the following procedure. A dry flask charged with4-(2-chloro-ethoxy)-phenylamine (6.7 mmol) (from Example 2c), p-TSA (6.7mmol), 2-chloro-5-bromo-pyrimidine (6.7 mmol), and NMP (5 mL) is heatedin a microwave oven at 210° C. for 15 min. The reaction mixture isdiluted with water and extracted with EtOAc (5×70 mL). The organic layeris washed with water, brine, dried over Na₂SO₄, and concentrated.Purification by automated silica chromatography using a mixture ofEtOAc:Hexane affords5-bromo-pyrimidin-2-yl)-[4-(2-chloro-ethoxy)-phenyl-amine (33%). ¹HNMR(400 MHz, CDCl₃) δ 8.35 (s, 2H), 7.39-7.33 (m, 2H), 7.19 (s, 1H), 6.86(m, 2H), 4.15 (t, J=6.0 Hz, 2H), 3.74 (t, J=6.0 Hz, 2H). MS (m/z) (M+1)⁺329.1.

Example 3d(5-Bromo-pyrimidin-2-yl)-[-(2-morpholin-4-yl-ethyl)-phenyl]-amine

(5-Bromo-pyrimidin-2-yl)-[-(2-morpholin-4-yl-ethyl)-phenyl]-amine can besynthesized by the following procedure. A dry flask charged with4-(2-morpholin-4-yl-ethyl)-phenylamine (6.1 mmol) (from Example 2d),p-TSA (6.1 mmol), 2-chloro-5-bromo-pyrimidine (6.1 mmol) in NMP (5 mL)is heated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (5×70 mL). Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated. Purification by silica chromatography(DCM:MeOH:NH₄OH=95:5:0.1) affords(5-bromo-pyrimidin-2-yl)-[-(2-morpholin-4-yl-ethyl)-phenyl]-amine (50%).¹HNMR (400 MHz, DMSO-d₆) δ 9.75 (S, 1H), 8.58 (s, 2H), 7.60 (d, J=8.4Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 3.59 (t, J=4.4 Hz, 4H), 2.69 (t, J=8.0Hz, 2H), 2.49 (t, J=8.0 Hz, 2H), 2.34 (m, 4H). MS (m/z) (M+1)⁺ 363.1.

Example 3e(5-Bromo-pyrimidin-2-yl)-[3-(2-diethylamino-ethoxy)-phenyl]-amine

(5-Bromo-pyrimidin-2-yl)-[3-(2-diethylamino-ethoxy)-phenyl]-amine can besynthesized by the following procedure. A 25 ml flask is charged with3-(2-diethylamino-ethoxy)-phenyl]-amine (1.7 mmol),2-chloro-5-bromo-pyrimidine (1.7 mmol), p-TSA (1.7 mmol) and NMP (2 mL).The flask is evacuated and irradiated in a microwave oven at 210° C. for15 min. The reaction mixture is diluted with water and extracted with aEtOAc:THF 4:1 solution (5×50 mL). The organic layer is washed withbrine, dried over Na₂SO₄, and concentrated. Purification by HPLC (ACNgradient 10-90%) affords the title compounds (63%). MS (m/z) (M+1)⁺366.1.

Example 3f 4-(5-Bromo-pyrimidin-2-ylamino)-benzoic acid methyl ester

4-(5-Bromo-pyrimidin-2-ylamino)-benzoic acid methyl ester can besynthesized by the following procedure. A 25 ml flask is charged withp-amino methyl benzoate (3.3 mmol) 2-chloro-5-bromo-pyrimidine (3.3mmol), p-TSA (1.5 mmol) and NMP (2 mL). The flask is evacuated andirradiated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (5×50 mL). Theorganic layer is washed with brine, dried over Na₂SO₄, and concentrated.Purification by HPLC (ACN gradient 10-90%) affords the title compounds(30%). ¹HNMR (400 MHz, DMSO-d₆) δ 10.34 (s, 1H), 8.70 (s, 2H), 7.92-7.86(m, 4H), 3.82 (s, 3H). MS (m/z) (M+1)⁺ 308.1.

Example 3g 5-(5-Bromo-pyrimidin-2-ylamino)-2-methoxy-phenol

5-(5-Bromo-pyrimidin-2-ylamino)-2-methoxy-phenol can be synthesized bythe following procedure. A 25 ml flask is charged with5-amino-2-methoxy-phenol (3.5 mmol) 2-chloro-5-bromo-pyrimidine (3.5mmol), p-TSA (1 mmol) and NMP (2 mL). The flask is evacuated andirradiated in a microwave oven at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with DCM (5×50 mL). Theorganic layer is washed with brine, dried over Na₂SO₄, and concentrated.Purification by HPLC (ACN gradient 10-90%) affords the title compounds(25%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 8.51 (s, 2H), 7.18 (d,J, 4 Hz, 1H), 7.02 (dd, J=8.0 and 4.0 Hz, 1H), 6.83 (d, J=8.0 Hz, 1H),3.72 (s, 3H), 3.17 (s, 1H). MS (m/z) (M+1)⁺ 297.1.

Example 3h [4-(5-Bromo-pyrimidin-2-ylamino)-phenyl]-methanol

[4-(5-Bromo-pyrimidin-2-ylamino)-phenyl]-methanol can be synthesized bythe following procedure. To a solution of 4-aminobenzyl alcohol (8.12mmol) and 5-bromo-2-chloro-pyrimidine (9.74 mmol) in 2-propanol (20 mL)is added sodium iodide (8.12 mmol) and diisopropylethylamine (16.2mmol). The reaction mixture is heated in the microwave oven at 200° C.for 15 min. Purification by silica chromatography using hexane:EtOAc=7:3affords [4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol (44%). ¹HNMR(400 MHz, CDCl₃) δ 8.36 (s, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.28 (d, J=8.4Hz, 2H) 7.07 (bs, 1H), 4.60 (s, 2H). MS (m/z) (M+1)⁺ 280.3.

Example 3i 4-Methyl-piperazine-1-carboxylic acid4-(5-bromo-pyrimidin-2-ylamino)-phenyl ester

4-Methyl-piperazine-1-carboxylic acid4-(5-bromo-pyrimidin-2-ylamino)-phenyl ester can be synthesized by thefollowing procedure. To a solution of 4-methyl-piperazine-1-carboxylicacid 4-amino-phenyl ester (1.06 mmol) (from Example 2f) in NMP (2 mL)are added 5-bromo-2-chloro-pyrimidine (1.06 mmol) and pTSA (1.06 mmol).The flask is evacuated twice and heated in a microwave oven at 210° C.for 10 min. The reaction mix is diluted with water and extracted withDCM. The organic layer is washed with water, brine, dried over Na₂SO₄and concentrated. The crude mixture is purified by HPLC (ACN gradient10-90) to afford 4-methyl-piperazine-1-carboxylic acid4-(5-bromo-pyrimidin-2-ylamino)-phenyl ester (25%). MS (m/z) (M+1)⁺393.25.

Example 3l 2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)ethanol

2-(4-(5-Bromopyrimidin-2-ylamino)phenyl)ethanol can be synthesized bythe following procedure. A mixture of 2-(4-aminophenyl)ethanol (0.72mol), 2-chloro-5-bromo-pyrimidine (0.72 mol), NaI (0.72 mol), anddiisopropylethylamine (1.45 mol) in n-butanol (400 mL) is heated atreflux overnight. The reaction is cooled to rt and the mixture isdiluted with water. The light yellow solid that precipitates is filteredto give 2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol (57%). ¹HNMR(300 MHz, DMSO-d₆) δ 9.722 (s, 1H), 8.52 (s, 2H), 7.55 (m, 2H), 7.09 (d,2H), 4.64 (m, 1H), 3.52 (m, 2H), 2.65 (m, 2H).

Example 4 Synthesis of 5-substituted-2-choropyrimidine compounds Example4a 4-(2-Chloropyrimidin-5-yl)benzaldehyde

4-(2-Chloropyrimidin-5-yl)benzaldehyde can be synthesized by thefollowing procedure. To a solution of 2-chloro-5-bromo pyrimidine (2.58mmol) in DMF (2 mL) are added 4-formyl boronic acid (2.84 mmol), K₂CO₃(5.96 mmol of a 5M aq solution) and Pd(PPh₃)₄ (0.129 mmol). The reactionis evacuated twice and heated at 120° C. for 5 min. The reaction mixtureis diluted with a sat. aq NH₄Cl and extracted with DCM (3×50 mL). Theorganic layer is washed with brine, dried over Na₂SO₄ and concentrated.Purification by silica chromatography using hexane:EtOAc=8:2 affords4-(2-chloropyrimidin-5-yl)benzaldehyde (53%).

Example 4b Tert-butyl 2-(4-(2-chloropyrimidin-5-yl)benzylamino)acetate

Tert-butyl 2-(4-(2-chloropyrimidin-5-yl)benzylamino)acetate can besynthesized by the following procedure. To a solution of4-(2-chloropyrimidin-5-yl)benzaldehyde (1.37 mmol) (from Example 4a),phenylglycine tert-butylester (1.37 mmol) and diisopropylethylamine(1.64 mmol) in DCM (20 mL) is added MgSO₄ and the mixture is stirredovernight. MgSO₄ is filtered and the filtrate is diluted with a sat. aqNH₄Cl and extracted with DCM (3×50 mL). The organic layer is washed withbrine, dried over Na₂SO₄ and concentrated. Purification by silicachromatography using a hexane EtOAc=8:2 affords tert-butyl2-(4-(2-chloropyrimidin-5-yl)benzylamino)acetate (33%).

Example 4c 2-Chloro-5-(4-methoxy-phenyl)-pyrimidine

2-Chloro-5-(4-methoxy-phenyl)-pyrimidine can be synthesized by thefollowing procedure. To a solution of 2-chloro-5-bromo pyrimidine (7.7mmol) in DMF (1.5 mL), 4-methoxy boronic acid (8.9 mmol), K₂CO₃ (16.2mmol of a 5M aq solution) and Pd(PPh₃)₄ (0.38 mmol) are added. Thereaction is evacuated twice and heated at 120° C. for 5 min. After thistime the reaction mixture is diluted with a sat. aq NH₄Cl and extractedwith DCM (3×50 mL). The organic layer is washed with brine, dried overNa₂SO₄ and concentrated. Purification by silica chromatography using ahexane:EtOAc=8:2 affords 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (59%).¹HNMR (400 MHz, CDCl₃) δ 8.79 (s, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.05 (d,J=8.0 Hz, 2H), 3.87 (s, 3H). MS (m/z) (M+1)⁺ 221.1.

Example 4d 4-(2-Chloro-pyrimidin-5-yl)-benzoic acid

4-(2-Chloro-pyrimidin-5-yl)-benzoic acid can be synthesized by thefollowing procedure. To a solution of 2-chloro-5-bromo pyrimidine (9.9mmol) in DMF (10 mL) are added benzoic acid-4-boronic acid (10.9 mmol),K₂CO₃ (20.8 mmol of a 5M aq solution) and Pd(PPh₃)₄ (0.49 mmol). Thereaction is evacuated twice and heated at 80° C. for 2 h. Addition withwater promotes the separation of the desired compound. The solid iswashed with water and dried under vacuum to afford4-(2-chloro-pyrimidin-5-yl)-benzoic acid (51%). MS (m/z) (M+1)⁺ 235.1.

Example 5 Synthesis of 5-substituted-2-aminopyrimidine compounds Example5a[4-(2-Diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[4-(2-diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. To a solution of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine (0.32mmol) (from Example 3a) in glyme (1 mL) is added 4-methoxyphenylboronicacid (0.33 mmol), aqueous potassium carbonate (0.57 mmol), and Pd(PPh₃)₄(0.027 mmol). The reaction is heated at reflux for 15 min and thesolvent is removed. The residue is dissolved in DCM, washed with sat. aqNH₄Cl (2×20 mL), dried over Na₂SO₄, and concentrated. Purification byHPLC (ACN gradient 10-90%) affords the title compound (47%). The productis dissolved in MeOH and treated with MeSO₃H (1 eq) to afford[4-(2-diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amineas its mesylate salt (quantitative). ¹HNMR (400 MHz, MeOD) δ 8.64 (s,2H), 7.50-7.47 (m, 4H), 7.02-6.96 (m, 4H), 4.29 (t, J=4.8 Hz, 2H), 3.75(s, 3H), 3.54 (t, J=4.8 Hz, 2H), 3.33-3.24 (m, 4H), 2.61 (s, 3H), 1.30(t, J=7.2 Hz, 6H). MS (m/z) (M+1)⁺ 393.3.

Example 5b[4-(2-Diethylamino-ethylsulfanyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[4-(2-Diethylamino-ethylsulfanyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. To a solution of(5-bromo-pyridin-2-yl)-[4-(2-diethylamino-ethylsulfanyl)-phenyl]-amine(0.32 mmol) (from Example 3b) in glyme (1 mL) is added4-methoxyphenylboronic acid (0.33 mmol), aqueous potassium carbonate(0.57 mmol), and Pd(PPh₃)₄ (0.027 mmol). The reaction is heated atreflux for 15 min and the solvent is removed. The residue is dissolvedin DCM, washed with sat aq NH₄Cl. (2×20 mL), dried over Na₂SO₄, andconcentrated. Purification by HPLC (ACN gradient 10-90%) affords thetitle compound. The product is dissolved in MeOH and treated with MeSO₃H(1 eq) to afford[4-(2-diethylamino-ethylsulfanyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amineas its mesylate salt (quantitative). ¹HNMR (400 MHz, CD₃OD) δ 8.69 (s,2H) 7.82-7.80 (m, 2H), 7.55-7.48 (m, 4H), 7.05-7.03 (m, 2H), 3.84 (s,3H), 3.24-3.18 (m, 8H), 2.70 (s, 3H), 1.25 (t, J=8.0 Hz, 6H). MS (m/z)(M+1)⁺ 409.2.

Example 5c[5-(4-Methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethyl)-phenyl]-amine

[5-(4-Methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethyl)-phenyl]-aminecan be synthesized by the following procedure. To a solution of(5-bromo-pyrimidin-2-yl)-[-(2-morpholin-4-yl-ethyl)-phenyl]-amine (0.32mmol) (from Example 3d) in glyme (1 mL) is added 4-methoxyphenylboronicacid (0.33 mmol), aqueous potassium carbonate (0.57 mmol), and Pd(PPh₃)₄(0.027 mmol). The reaction is heated at reflux for 15 min and thesolvent is then removed. The residue is dissolved in DCM, washed withsat. aq NH₄Cl (2×20 mL), dried over Na₂SO₄, and concentrated.Purification by HPLC (ACN gradient 10-90%) affords[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethyl)-phenyl]-aminewhich is converted to the corresponding hydrochloride salt by treatmentwith 4N HCl. ¹HNMR (400 MHz, CD₃OD) δ 8.65 (s, 2H), 7.56-754 (m, 2H),7.49-7.46 (m, 2H), 7.27-7.25 (m, 2H), 6.97-6.95 (m, 2H), 4.02 (t, J=4.3Hz, 2H), 3.74 (s, 3H), 3.72 (t, J=4.3 Hz, 2H), 3.48 (d, J=4.3 Hz, 2H),3.34-3.30 (m, 2H), 3.16-3.10 (m, 2H), 3.03-2.99 (m, 2H). MS (m/z) (M+1)⁺391.2.

Example 5d[4-(2-Chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[4-(2-Chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. To a solution of5-bromo-pyrimidin-2-yl)-[4-(2-chloro-ethoxy)-phenyl-amine (0.32 mmol)(from Example 3c) in glyme (1 mL) is added 4-methoxyphenylboronic acid(0.33 mmol), aqueous potassium carbonate (0.57 mmol), and Pd(PPh₃)₄(0.027 mmol). The reaction is heated at reflux for 15 min and thesolvent is removed. The residue is dissolved in DCM, washed with sat. aqN₄HCl (2×20 mL), dried over Na₂SO₄, and concentrated. Purification byHPLC (ACN gradient 10-90%) gives the[4-(2-chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine.¹HNMR (400 MHz, CDCl₃) δ 8.53 (s, 2H), 7.50 (d, J=8.8 Hz, 2H), 7.43 (d,J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 4.17 (t,J=5.2 Hz, 2H), 3.79-3.77 (m, 5H). MS (m/z) (M+1)⁺ 356.2.

Example 5e(5-(4-Methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethoxy-phenyl-amine

(5-(4-Methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethoxy-phenyl]-aminecan be synthesized by the following procedure. A dry flask charged with[4-(2-chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine(0.14 mmol) (from Example 5d), NaI (0.14 mmol), morpholine (0.14 mmol),diisopropylethylamine (0.14 mmol) and DMF (0.5 mL) is heated in themicrowave oven at 200° C. for 8 min. The reaction is diluted with waterand extracted with EtOAc (5×20 mL). The organic layer is washed withwater, brine, dried over Na₂SO₄, and concentrated. Purification by HPLC(ACN gradient 10-90%) affords(5-(4-methoxy-phenyl)-pyrimidin-2-yl]-[4-(2-morpholin-4-yl-ethoxy-phenyl]-amine(36%) as a triflate salt. ¹HNMR (400 MHz, CDCl₃) δ 10.04 (s, 1H), 9.58(s, 2H), 7.73-7.69 (m, 2H), 7.69-7.60 (m, 2H), 7.05-6.96 (m, 4H),4.62-3.98 (brm 4H), 3.79 (s, 3H), 3.75-3.72 (brm, 2H), 3.61-3.50 (brm,4H), 3.21 (brm, 2H). MS (m/z) (M+1)⁺ 407.1.

Example 5f4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}benzaldehyde

4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzaldehydecan be synthesized by the following procedure. To a solution of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-amine (2 g,5.48 mmol) (from Example 3a) in THF:water (30 mL: 15 mL) is added4-formyl-phenylboronic acid (6 mmol), K₂CO₃ (12 mmol) and Pd(PPh₃)₂Cl₂(0.25 mmol). The reaction mixture is heated at 65° C. for 2 h. Afterremoval of the THF, the residue is diluted with dichloromethane andwater. Then the organic layer is separated, dried over sodium sulfate,and concentrated. Further purification by silica chromatography(DCM:MeOH=20:80) affords the4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzaldehyde(80%). MS (m/z) (M+1)⁺ 391.2.

Example 5g4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzaldehyde

4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzaldehydecan be synthesized by the following procedure. To a solution of(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-amine (5.48mmol) (from Example 3a) in THF:water (30 mL: 15 mL) is added3-fluoro-4-formyl-phenyl-boronic acid (6 mmol), K₂CO₃ (12 mmol) andPd(PPh₃)₂Cl₂ (0.25 mmol). The reaction mixture is heated at 65° C. for 2h. After removal of the THF, the residue is diluted with dichloromethaneand water. Then the organic layer is separated, dried over sodiumsulfate, and concentrated. Further purification by silica chromatography(DCM:MeOH=20:80) affords the4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzaldehyde(75%). MS (m/z) (M+1)⁺ 409.2.

Example 5h(5-{4-[(2-Tert-Butoxy-ethylamino)-methyl]-phenyl}-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-amine

(5-{4-[(2-Tert-butoxy-ethylamino)-methyl]-phenyl}-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-aminecan be synthesized by the following procedure. A solution of4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzaldehyde(0.05 mmol) (from Example 5f) and 2-tert-butoxy-ethylamine (0.1 mmol) in1 mL dichloromethane is stirred at rt for 1 h. Then NaB(OAc)₃H (0.15mmol) is added and the reaction is stirred for 5 h. Purification bypreparative LCMS affords(5-{4-[(2-tert-butoxy-ethylamino)-methyl]-phenyl}-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-amineas a TFA salt. MS (m/z) (M+1)⁺ 492.2.

Example 5i(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzylamino)-aceticacid tert-butyl ester

(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzylamino)-aceticacid tert-butyl ester can be synthesized by the following procedure. Asolution of4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzaldehyde(0.05 mmol) (from Example 5g) and amino-acetic acid tert-butyl ester(0.1 mmol) in 1 mL dichloromethane is stirred at rt for 1 h. ThenNaB(OAc)₃H (0.15 mmol) is added and the reaction is stirred for 5 h.Purification by preparative LCMS affords(4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzylamino)-aceticacid tert-butyl ester as a TFA salt. MS (m/z) (M+1)⁺ 524.2.

Example 5j 4-Methyl-piperazine-1-carboxylic acid3-(5-{4-[(tert-butoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester

4-Methyl-piperazine-1-carboxylic acid3-(5-{4-[(tert-butoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester can be synthesized with the following procedure.

A mixture of palladium acetate (0.01 mmol), Xantphos (0.012 mmol),potassium tert-butoxide (0.2 mmol),[4-(2-chloro-pyrimidin-5-yl)-benzylamino]-acetic acid tert-butyl ester(0.1 mmol) (from Example 4b) and 3-aminophenyl4-methylpiperazine-1-carboxylate (from Example 2e) (0.3 mmol) in dioxane(1 mL) is heated at 90° C. for 1 h. Purification is done usingpreparative LCMS to afford 4-methyl-piperazine-1-carboxylic acid3-(5-{4-[(tert-butoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester as a TFA salt. MS (m/z) (M+1)⁺ 533.0.

Example 5k 4-Methyl-piperazine-1-carboxylic acid4-(5-{4-[(tert-butoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester

4-Methyl-piperazine-1-carboxylic acid4-(5-{4-[(tert-butoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester can be synthesized by the following procedure. A mixture ofPalladium acetate (0.01 mmol), Xantphos (0.012 mmol), potassiumtert-butoxide (0.2 mmol),[4-(2-chloro-pyrimidin-5-yl)-benzylamino]-acetic acid tertbutyl ester(0.1 mmol) (from Example 4b) and 4-aminophenyl4-methylpiperazine-1-carboxylate (from Example 2f) (0.3 mmol) in dioxane(1 mL) is heated at 90° C. for 1 h. Purification by preparative LCMS toaffords 4-methyl-piperazine-1-carboxylic acid4-(5-{4-[(tertbutoxycarbonylmethyl-amino)-methyl]-phenyl}-pyrimidin-2-ylamino)-phenylester as a TFA salt. MS (m/z) (M+1)⁺ 532.4.

Example 5l 4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid

4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid can beprepared by the following procedure. To a solution of4-(5-bromo-pyrimidin-2-ylamino)-benzoic acid methyl ester (0.3 mmol)(from Example 3f) in DMF (1.5 mL) are added 4-methoxy boronic acid (0.3mmol), aq K₂CO₃ (0.68 mmol) and Pd(PPh₃)₄ (0.16 mmol). The reactionmixture is evacuated twice and heated at 80° C. for 30 min. After thistime the reaction mixture is diluted with a sat. aq NH₄Cl and extractedwith DCM (3×30 mL). The organic layer is washed with brine, dried overNa₂SO₄ and concentrated to afford4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid methyl esterthat upon trituration with MeOH gives an orange solid (95%). MS (m/z)(M+1)⁺ 336.1. This solid is suspended in a 3:2:1=THF:MeOH:H₂O solution(3 mL) and 6N LiOH (0.15 mL) added and stirred at rt for 12 h. At thispoint the solvent is removed and the residue is dissolved in water andextracted with DCM (3×30 mL). The mixture is adjusted to pH ˜2 andextracted with a 3:1=DCM:IPA mixture (5×30 mL). The organic layer iswashed with brine, dried over Na₂SO₄ and concentrated to afford4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid as an orangepowder (100%) which is used without further purification. ¹HNMR (400MHz, DMSO-d₆) δ 10.18 (s, 1H), 8.87 (s, 2H), 7.95-7.87 (m, 4H), 7.71 (d,J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 3.81 (s, 3H). MS (m/z) (M+1)⁺322.1.

Example 5m1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzoyl}-piperidine-4-carboxylicacid amide

1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzoyl}-piperidine-4-carboxylicacid amide can be synthesized by the following procedure. To a solutionof 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid (fromExample 5l) (0.05 mmol) in anhydrous DMF (1 mL) is added HATU (0.06mmol), diisopropylethylethylamine (0.12 mmol) andpiperidine-4-carboxylic acid amide (0.08 mmol). The reaction mixture isstirred at rt for 8 h. The reaction mixture is purified by HPLC (ACNgradient 10-80%) to afford1-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoyl}-piperidine-4-carboxylicacid amide (30%) as a fluffy off white solid. MS (m/z) (M+1)⁺ 432.2.

Example 5n(3-Hydroxy-pyrrolidin-1-yl)-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanone

(3-Hydroxy-pyrrolidin-1-yl)-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanonecan be synthesized by the following procedure. To a solution of4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoic acid (from Example5l) (0.05 mmol) in anhydrous DMF (1 mL), HATU (0.06 mmol),diisopropylethylethylamine (0.12 mmol) and pyrrolidin-3-ol (0.08 mmol).The reaction mixture is stirred at rt for 8 h. The reaction mixture ispurified by HPLC (ACN gradient 10-80%) to afford the title compound.¹HNMR (400 MHz, DMSO) δ 10.00 (s, 1H), 8.85 (s, 2H), 7.88-7.85 (m, 2H),7.69-7.66 (m, 2H), 7.52-7.49 (m, 2H), 7.07-7.05 (m, 2H), 5.01-4.92 (m,1H), 4.33-4.23 (m, 1H), 3.81 9 s, 3H), 3.67-3.45 9 m, 4H), 1.94-1.80 (m,2H). MS (m/z) (M+1)⁺ 391.2.

Example 5o4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoicacid

4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoicacid can be synthesized by the following procedure. To a solution of4-(5-bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl]-amine (1.1mmol) (from Example 3a) in DME (2 mL) are added4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (1.3 mmol),K₂CO₃ aq. (2.3 mmol) and Pd(PPh₃)₄ (0.11 mmol). The reaction isevacuated and heated at 80° C. for 1 h. The reaction mixture is dilutedwith a sat. aq NH₄Cl and extracted with DCM (3×30 mL). The organic layeris washed with brine, dried over Na₂SO₄ and concentrated to afford adark residue that upon trituration with MeOH gives a gray solid (25%)that is used without further purification. MS (m/z) (M+1)⁺ 407.3.

Example 5p(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoylamino)-aceticacid tert-butyl ester

(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoylamino)-aceticacid tert-butyl ester can be synthesized by the following procedure. Toa solution of4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoicacid (from Example 5o) (0.195 mmol) in anhydrous DMF (1.5 mL) is addedHATU (0.273 mmol), diisopropylethylethylamine (0.273 mmol) and glycinetert-butyl ester (0.2 mmol). The mixture is stirred at rt for 8 h. Thereaction mixture is quenched with a 10% aq K₂CO₃ and extracted with DCM.Purification by HPLC (ACN gradient 10-90%) affords(4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoylamino)-aceticacid tert-butyl ester as triflate salt (32%). ¹HNMR (400 MHz, DMSO-d₆) δ9.78 (s, 1H), 9.40 (bs, 1H), 8.91 (t, J=4 Hz, 1H), 8.89 (s, 2H), 7.97(d, J, 8 Hz, 2H), 7.85 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 6.99(d, J=8.0 Hz, 2H), 4.29 (t, J=4.0 Hz, 2H), 3.92 (d, J=4 Hz, 2H),3.55-3.51 (m, 2H), 3.27-3.22 (m, 4H), 1.25 (t, J=4.0 Hz, 6H). MS (m/z)(M+1)⁺ 520.2.

Example 5q[3-(2-Diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[3-(2-Diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. To a solution of(5-bromo-pyrimidin-2-yl)-[3-(2-diethylamino-ethoxy)-phenyl]-amine (0.29mmol) (from Example 3e) in DME (2 mL) are added 4-methoxy boronic acid(0.35 mmol), aq K₂CO₃ (0.66 mmol) and Pd(PPh₃)₄ (0.029 mmol). Thereaction mixture is refluxed for 30 min. After removal of DME, theresidue is dissolved in DCM and washed with a sat. aq NH₄Cl. The organiclayer is dried over Na₂SO₄ and concentrated under reduced pressure.Purification of the crude by HPLC (ACN gradient 10-90%) affords[3-(2-diethylamino-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine(70%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.65 (bs 1H), 8.79 (s,2H), 7.66 (d, J=8.0 Hz, 2H), 7.61 (m, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.24(t, J=8.0 Hz, 1H), 7.04 (d, J=8.0 Hz, 2H), 6.62 (d, J=8.0 Hz, 1H),4.34-4.32 (m, 2H), 3.80 (s, 3H), 3.57-3.55 (m, 2H), 3.28-3.23 (m, 4H),1.26 (t, j=8.0 Hz, 3H). MS (m/z) (M+1)⁺ 393.2.

Example 5r 3-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol

3-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenol can be prepared bythe following procedure. A dry flask charged with 3-amino-phenol (0.18mmol), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (0.18 mmol) (fromExample 4c), diisopropylethylethylamine (0.09 mmol) in NMP is heated ina microwave oven at 210° C. for 10 min. The reaction mixture is dilutedwith water and extracted with DCM (3×20 mL), washed with brine, driedover Na₂SO₄ and concentrated. Purification by preparative LCMS (ACNgradient 10-70%) affords3-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol (22%). ¹HNMR (400MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.76 (s, 2H), 7.66-7.63 (m, 2H), 7.36 (t,J=4.0 Hz, 1H), 7.19-7.17 (m, 1H), 7.07-7.03 (M, 3H), 6.38-6.35 (M, 1H),3.80 (s, 3H). MS (m/z) (M+1)⁺ 294.1.

Example 5s 4-Methyl-piperazine-1-carboxylic acid3-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester

4-Methyl-piperazine-1-carboxylic acid3-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester can besynthesized by the following procedure. To a solution of3-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol (from Example 5r)(0.04 mmol) in DMF is added Cs₂CO₃ (0.09 mmol) followed by4-methyl-piperazine-1-carbonyl chloride (0.9 mmol). The reaction isstirred at rt for 12 h. The reaction mixture is directly purified bypreparative LCMS (ACN gradient 10-70%) to afford4-methyl-piperazine-1-carboxylic acid3-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester as TFA salt(30%). ¹HNMR (400 MHz, CD₃OD) δ 8.67 (s, 2H), 7.82 (t, J=4.0 Hz, 1H),7.54-7.52 (m, 2H), 7.47-7.46 (m, 1H), 7.30 (T, J=8.0 Hz, 1H), 7.05-7.02(m, 2H), 6.78-6.75 (m, 1H), 3.84 (s, 3H), 2.98 (s, 3H). MS (m/z) (M+1)⁺420.2.

Example 5t2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester

2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester can be synthesized by the following procedure. To asolution of 3-(2-diethylamino-ethoxy)-phenylamine (0.2 mmol) (fromExample 2h) in anhydrous dioxane (1.5 mL) is added Pd(OAc)₂ (0.03 mmol),xantphos (0.03 mmol), potassium tert-butoxide (0.4 mmol) and2-Cl-5(4-methoxyphenyl)pyrimidine (0.2 mmol) (from Example 4c). Thereaction mixture is evacuated twice and heated at 130° C. for 45 min.The reaction mixture is filtered and the filtrate concentrated.Purification by preparative LCMS (ACN gradient 10-40%) and subsequentpreparative TLC (DCM:ACN:MeOH:NH₄OH=8:1:1:0.1) affords2-(2-diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester (20%). MS (m/z) (M+1)⁺ 451.3.

Example 5u2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid

2-(2-Diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid can be synthesized by the following procedure. To a suspension of2-(2-diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid methyl ester (0.022 mmol) (from example 5t) in a 3:2:1=THF:MeOH:H₂Osolution (1 mL) is added 3N LiOH (22 μL) and the mixture is stirred atrt for 12 h then solvent is removed. Purification of the crude bypreparative LCMS (ACN gradient 10-50%) affords2-(2-diethylamino-ethoxy)-4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid. ¹HNMR (400 MHz, CD₃OD) δ 18.76 (s, 2H), 7.99 (bs, 1H), 7.89 (d,J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.05 (d,J=8.0 Hz, 2H), 4.53-4.53 (m, 2H), 3.84 (s, 3H), 3.66-3.63 (m, 2H),3.40-3.37 (m, 4H), 1.38 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 437.1.

Example 5v 2-Methoxy-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol

2-Methoxy-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol can besynthesized by the following procedure. To a solution of5-(5-bromo-pyrimidin-2-ylamino)-2-methoxy-phenol (0.34 mmol) (formExample 3g) in DMF (1.5 mL) is added 4-methoxy boronic acid (0.41 mmol),K₂CO₃ aq. (0.71 mmol) and Pd(PPh₃)₄ (0.17 mmol). The reaction isevacuated twice and heated at 85° C. for 30 min. After this time thereaction mixture is diluted with a sat. aq NH₄Cl and extracted with DCM(3×30 mL). The organic layer is washed with brine, dried over Na₂SO₄,concentrated and the crude is purified by HPLC (ACN gradient 20-70%)(67%). MS (m/z) (M+1)⁺ 324.1.

Example 5wN-(3-(2-(diethylamino)ethoxy)-4-methoxyphenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine

[3-(2-Diethylamino-ethoxy)-4-methoxy-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. To a solution of2-methoxy-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenol (0.2 mmol)(from Example 5v) in anhydrous DMF (2 mL) is added Cs₂CO₃ (0.28 mmol)and (2-chloro-ethyl)-diethyl-amine (0.2 mmol). The reaction mixturestirred at 80° C. for 8 h and quenched with water followed by extractionwith DCM (3×30 mL). The organic layer is washed with brine, dried overNa₂SO₄ and concentrated. Preparative LCMS purification affords the titlecompound (78%). MS (m/z) (M+1)⁺ 423.1.

Example 5x1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid

1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid can be synthesized by the following procedure. To a solution of[4-(2-chloro-ethoxy)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine(0.042 mmol) (from Example 5d) in DMF (1 ml) is added sodium iodide(0.050 mmol) and ethyl isonipecotate (0.084 mmol). The reaction isheated at 120° C. for 12 h. Purification by HPLC (ACN gradient 10-90%)affords1-(2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid ethyl ester (50%). MS (m/z) (M+1)⁺ 477.0. This solid is suspendedin a 3:2:1=THF:MeOH:H₂O solution (0.5 mL) and 6N LiOH (0.126 mmol) andstirred at rt for 12 h. The reaction mixture is diluted with DMF andpurified by HPLC (ACN gradient 10-90%) to afford1-(2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenoxy}-ethyl)-piperidine-4-carboxylicacid. MS (m/z) (M+1)⁺ 449.2.

Example 5y(4-{2-[4-(2-Chloro-ethoxy)-benzyl]-pyrimidin-5-yl}-benzylamino)-aceticacid tert-butyl ester

(4-{2-[4-(2-Chloro-ethoxy)-benzyl]-pyrimidin-5-yl-benzylamino)-aceticacid tert-butyl ester can be synthesized by the following procedure. Amixture of palladium acetate (0.015 mmol), Xantphos (0.018 mmol),potassium tert-butoxide (0.3 mmol), tert-butyl2-(4-(2-chloropyrimidin-5-yl)benzylamino)acetate (0.15 mmol) (fromExample 4b) and 4-(2-chloro-ethoxy)-phenylamine (from Example 2c) (0.45mmol) in dioxane (2 mL) is heated in the microwave oven at 150° C. for15 min. Purification by preparative LCMS to afford(4-{2-[4-(2-chloro-ethoxy)-benzyl]-pyrimidin-5-yl}-benzylamino)-aceticacid t-butyl ester as a TFA salt. MS (m/z) (M+1)⁺ 469.2.

Example 5z{4-[2-(4-{{2-[4-(Tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino]-aceticacid tert-butyl ester

{4-[2-(4-{{2-[4-(Tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino]-aceticacid tert-butyl ester can be synthesized by the following procedure. Toa solution of(4-{2-[4-(2-chloro-ethoxy)-benzyl]-pyrimidin-5-yl}-benzylamino)-aceticacid tert-butyl ester (0.032 mmol) (from Example 5y) in anhydrous DMF isadded sodium iodide (0.0384 mmol) and 1-(tetrahydro-2-furoyl)-piperazine(0.16 mmol). The reaction mixture is heated at 90° C. for 8 h.Purification by preparative LCMS (ACN gradient 10-90%) affords{4-[2-(4-{2-[4-(tetrahydro-furan-2-carbonyl)-piperazin-1-yl]-ethoxy}-benzyl)-pyrimidin-5-yl]-benzylamino}-aceticacid tert-butyl ester (51%). ¹H NMR (400 MHz, CDCl₃) δ 7.66 (d, J=8.0Hz, 2H), 7.62 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.0Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 6.85 (d, J=9.2 Hz, 2H), 4.3 (m, 4H),3.85 (m, 4H), 3.76 (m, 3H), 3.52 (m, 4H), 2.35 (m, 4H), 2.0 (m, 4H),1.48 (s, 9H). MS (m/z) (M+1)⁺ 617.2.

Example 6 Example 6a{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanol

{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanol can besynthesized by the following procedure. To a solution of[4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol (7.14 mmol) (fromExample 3h) in DMF (56 mL) is added 4-methoxy boronic acid (8.57 mmol),K₂CO₃ aq (21.4 mmol) and Pd(PPh₃)₄ (0.714 mmol). The reaction isevacuated twice and heated at 90° C. for 1 h. After this time thereaction mixture is diluted with a sat. aq NH₄Cl and extracted withethyl acetate (3×50 mL). The organic layer is washed with brine, driedover MgSO₄ and concentrated. Purification by silica chromatography usinga hexane:EtOAc=8:2 affords{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanol (80%). ¹HNMR (400 MHz, CDCl₃) δ 8.57 (s, 2H), 7.57 (d, J=8 Hz, 2H), 7.45 (bs,1H), 7.37 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.94 (d, J=8.4 Hz,2H), 4.61 (s, 2H), 3.79 (s, 3H). MS (m/z) (M+1) 308.3.

Example 6b 4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde

4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde can besynthesized by the following procedure. To a mixture of{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanol (5.73mmol) (from Example 5aa) in dioxane is added manganese (IV) oxide (17.2mmol) and TBAI (0.014 mmol). The reaction mixture is heated in themicrowave oven at 130° C. for 30 min. Purification by silicachromatography using hexane:EtOAc=1:1 affords4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde (52%). ¹H NMR(400 MHz, CDCl₃) δ 9.91 (s, 1H), 8.69 (s, 2H), 7.88 (s, 4H), 7.46 (d,J=8.8 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 3.87 (s, 3H). MS (m/z) (M+1)⁺306.2.

Example 6c1-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidine-4-carboxylicacid amide

1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidine-4-carboxylicacid amide can be synthesized by the following procedure. To a solutionof 4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde (0.0328mmol) (from Example 5ab) in dichloromethane (1 mL) is addedisonipecotamide (0.0768 mmol) and sodium sulfate. The reaction mixtureis stirred at rt for 1 h. Then NaB(OAc)₃H (0.0984 mmol) is added and thereaction is stirred for 8 h. Purification by preparative LCMS affords1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidine-4-carboxylicacid amide (55%) as a TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 8.72 (s, 2H),7.91 (d, J=8.4 Hz, 2H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (d, J=8.8 Hz, 2H),7.05 (d, J=8.8 Hz, 2H), 4.28 (s, 2H), 3.86 (s, 3H), 3.58 (m, 2H), 3.03(m, 2H), 2.55 (m, 1H), 2.10 (m, 2H), 1.93 (m, 2H). MS (m/z) (M+1)⁺418.2.

Example 6d(1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidin-4-yl)-aceticacid

(1-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidin-4-yl)-aceticacid can be synthesized by the following procedure. A mixture of4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde (0.0656 mmol)(from Example 5ab), 2-(piperidin-4-yl)acetic acid ethyl ester (0.197mmol) and sodium sulfate in dichloromethane (1 ml) is stirred at rt for1 h. Then NaB(OAc)₃H (0.197 mmol) is added and the reaction is stirredfor 8 h. Purification by preparative LCMS affords(1-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidin-4-yl)-aceticacid ethyl ester as a TFA salt (46%). MS (m/z) (M+1)⁺ 461.3. This solidis suspended in a 3:2:1=THF:MeOH:H₂O solution (0.6 mL) and 6N LiOH isadded (0.09 mmol). The mixture is stirred at rt for 12 h. The reactionmixture is diluted in DMF and purified by HPLC (ACN gradient 10-90%) toafford(1-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzyl}-piperidin-4-yl)-aceticacid (54%). ¹H NMR (400 MHz, CD₃OD) δ 8.70 (s, 2H), 7.88 (d, J=8.0 Hz,2H), 7.54 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.03 (d, J=8.4 Hz,2H), 4.25 (s, 2H), 3.84 (s, 3H), 3.5 (m, 2H), 3.3 (m, 2H), 2.3 (m, 2H),2.04 (m, 3H), 1.49 (m, 2H). MS (m/z) (M+1)⁺ 433.2.

Example 6e2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethanol

2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethanol can besynthesized by the following procedure. To a solution of2-(4-(5-bromopyrimidin-2-ylamino)phenyl)ethanol (0.204 mol) (fromExample 3l) in DME (200 mL) is added 4-methoxyphenylboronic acid (0.214mol), aq K₂CO₃ (0.408 mol) and Pd(PPh₃)₄ (172 mmol). The reaction isheated at reflux for 1 h, cooled to rt and the solvent evaporated. Theresidue is dissolved in dichloromethane, washed with sat. aq NH₄Cl(2×200 mL), dried over Na₂SO₄, and concentrated. Purification by silicachromatography (petroleum ether:EtOAc=1:1) affords2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethanol (46%).¹HNMR (300 MHz, DMSO-d₆) δ 8.59 (s, 2H), 7.57 (d, J=8.4 Hz, 2H), 7.43(d, J=9.0 Hz, 2H), 7.23 (d, J=8.4 Hz, 2H), 6.99 (d, J=9 Hz, 2H), 3.85(m, 5H), 2.86 (m, 2H).

Example 6f Methanesulfonic acid2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl ester

Methanesulfonic acid2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl ester canbe synthesized by the following procedure. To a solution of2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethanol (6.22mmol) in dichloromethane (30 mL) is added triethylamine (9.33 mmol) andmethanesulfonyl chloride (7.47 mmol). The reaction mixture is stirred atrt for 1.5 h. The reaction is diluted with H₂O (10 mL) and washed withNa₂CO₃ solution (3×10 mL). The organic layer is washed with brine, driedover MgSO4 and concentrated to afford methanesulfonic acid2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-3-phenyl}-ethyl ester(99%). ¹H NMR (400 MHz, CD₂Cl₂) δ 8.54 (s, 2H), 7.56 (d, J=8.8 Hz, 2H),7.39 (d, J=8.8 Hz, 2H), 7.29 (bs, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.92 (d,J=8.8 Hz, 2H), 4.31 (t, J=6.8 Hz, 2H), 3.76 (s, 3H), 2.95 (t, J=6.8 Hz,2H), 2.79 (s, 3H). MS (m/z) (M+1)⁺ 400.4.

Example 6g1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl)-piperidine-3-carboxylicacid amide

1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl)-piperidine-3-carboxylicacid amide can be synthesized according to the following procedure. To asolution of methanesulfonic acid2-{4[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl ester(0.050 mmol) in anhydrous DMF is added nipecotamide (0.25 mmol) andheated at 100° C. for 8 h. Purification by preparative LCMS affords1-(2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl)-piperidine-3-carboxylicacid amide (80%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 8.76 (s,2H), 7.75 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.20 (d, J=9.2 Hz,2H), 7.04 (d, J=8.8 Hz, 2H), 3.80 (s, 3H) 3.55 (m, 2H), 3.3 (m, 2H),2.95 (m, 4H), 2.6 (m, 1H), 1.95 (m, 2H), 1.70 (m, 2H). MS (m/z) (M+1)⁺432.3.

Example 6h 4-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoicacid

4-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoic acid can besynthesized according to the following procedure. To a solution of3-amino benzyl alcohol (8.1 mmol) in NMP (8 mL), in a microwave vial, isadded 4-(2-chloro-pyrimidin-5-yl)-benzoic acid (8.1 mmol) (from Example4d) and p-TSA (5.2 mmol). The vial is evacuated twice and then heated ina microwave oven at 210° C. for 15 min. The reaction mixture is quenchedwith water, the precipitated solid is filtered, washed with additionalwater, then EtOAc and dried under vacuum to afford4-[2-(3-hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoic acid (68%).¹H NMR (400 MHz, DMSO-d₆) δ 9.89 (s, 1H), 8.92 (s, 2H), 8.03-8.01 (m,2H), 7.88-7.86 (m, 2H), 7.76 (b.s, 1H), 7.70-68 (m, 1H), 7.26-7.24 (m,1H) 6.94-6.92 (m, 1H), 4.49 (m, 2H). MS (m/z) (M+1)⁺ 322.2.

Example 6i{4-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester

{4-[2-(3-Hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester can be synthesized according to the followingprocedure. A solution of4-[2-(3-hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoic (from Example5ah) (1.7 mmol), HATU (2.39 mmol), diisopropylethylamine (2.5 mmol), andglycine t-butyl ester in anhydrous DMF, is stirred at rt for 8 h. Afterthis time the reaction mixture is purified by HPLC (ACN gradient 10-90)to afford4-[2-(3-hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester (39%). MS (m/z) (M+1)⁺ 435.1.

Example 6j{4-[2-(3-Formyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-acetic acidtert-butyl ester

{4-[2-(3-Formyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-acetic acidtert-butyl ester can be synthesized by the following procedure. To amixture of{4-[2-(3-hydroxymethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester (0.39 mmol) (from example 5ai) in dioxane is addedmanganese (IV) oxide (1.95 mmol) and TBAI (0.014 mmol). The reactionmixture is heated in the microwave oven at 150° C. for 30 min. Thereaction mixture is filtered and the filtrated is concentrated underreduced pressure to afford{4-[2-(3-formyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-acetic acidtert-butyl ester (71%). MS (m/z) (M+1)⁺ 433.2.

Example 6k{4-[2-(3-Pyrrolidin-1-ylmethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester

{4-[2-(3-Pyrrolidin-1-ylmethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester can be synthesized by the following procedure. Toa solution{4-[2-(3-formyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-acetic acidtert-butyl ester (0.046 mmol) (from Example 5aj) in dichloromethane (1mL) is added pyrrolidine (0.138 mmol) and sodium sulfate. The reactionmixture is stirred at rt for 1 h. Then NaB(OAc)₃H (0.138 mmol) is addedand the reaction is stirred for 8 h. After this time the reactionmixture is purified by preparative LCMS to afford{4-[2-(3-pyrrolidin-1-ylmethyl-phenylamino)-pyrimidin-5-yl]-benzoylamino}-aceticacid tert-butyl ester (55%) as a TFA salt. ¹H NMR (400 MHz, DMSO-d₆) δ10.05 (s, 1H), 8.94-8.92 (m, 3H), 7.99-7.85 (m, 6H), 7.41 (m, 1H),7.14-7.12 (m, 1H), 4.35 (d, J=4.0 Hz, 2H), 3.93 (d, J=4.0 Hz, 2H),3.41-3.40 (m, 2H), 3.15-3.10 (m, 2H), 2.15-2.10 (m, 2H), 1.90-1.89 (m,2H), 1.43 (s, 9H). MS (m/z) (M+1)⁺ 488.3.

Example 6l 4-Methyl-piperazine-1-carboxylic acid4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester

4-Methyl-piperazine-1-carboxylic acid4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester can besynthesized by the following procedure. A suspension of4-methyl-piperazine-1-carboxylic acid 4-amino-phenyl ester (0.166 mmol)(from example 3i), 4-methoxy phenyl boronic acid (0.199 mmol), K₂CO₃(0.36 mmol) and Pd(PPh₃)₄ (0.0166 mmol) in a 5:1 mixture of DME:H₂O (1.5mL) is heated at 80° C. for 10 min. The reaction mixture is cooled tort, diluted with dichloromethane, washed with NH₄Cl, and dried underreduced pressure. The crude is purified by a short silica column using amixture 9.5:0.5:0.1=DCM:MeOH:NH₄OH to afford4-methyl-piperazine-1-carboxylic acid4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl ester as whitepowder (86%). ¹H NMR (400 MHz, CDCl₃) δ 8.53 (s, 2H), 7.57 (d, J=8.0 Hz,2H), 7.37 (d, J=8.0 Hz, 2H), 7.12 (b.s, 1H), 7.0.2 (m, 2H), 6.95 (m,2H), 3.79 (s, 3H), 3.71-3.69 (m, 4H), 2.51-2.50 (m, 4H). MS (m/z) (M+1)⁺420.2.

A methanolic solution of this solid is treated with 1 equivalent ofMeSO₃H and lyophilized to afford the correspondent mesylate salt asyellow solid in quantitative yield. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s,2H), 7.55-7.52 (m, 2H), 7.35-7.33 (m, 2H), 6.93-6.90 (m, 2H), 6.85-6.83(m, 2H), 4.30-4.28 (m, 2H), 3.64 (s, 3H), 3.41-3.40 (m, 2H), 2.94-2.91(m, 4H), 2.79 (s, 3H). MS (m/z) (M+1)⁺ 420.2.

Example 6mN-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amine

N-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-aminecan be prepared by the following procedure. To a mixture of2-chloro-5-(4-methoxy-phenyl)-pyrimidine (0.40 mmol) (from Example 4c)and 3-(2-(diethylamino)ethyl)benzenamine (0.40 mmol) (from example 2i)in 0.5 mL of 1,4-dioxane is added p-TSA monohydrate (1.2 mmol). Thereaction mixture is heated at 90° C. overnight. The crude mixture ispurified by preparative LCMS to affordN-(3-(2-(diethylamino)ethyl)phenyl)-5-(4-methoxyphenyl)pyrimidin-2-amineas a TFA salt. ¹H NMR (400 MHz, CD₃OD) δ 12.24 (s, 1H), 10.95 (s, 1H),8.67 (s, 2H), 7.50-7.60 (m, 2H), 7.26-7.44 (m, 3H), 7.04-7.12 (m, 1H),6.96-7.02 (m, 2H), 3.81 (s, 3H), 3.42 (m, 2H), 3.04-3.26 (m, 6H), 1.39(m, 6H). MS (m/z) (M+1)⁺ 377.2.

Example 6n 3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate

3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate can be prepared by the followingprocedure. To a mixture of 2-chloro-5-(4-methoxy-phenyl)-pyrimidine(0.40 mmol) (from Example 4c) and 3-aminobenzyl4-methylpiperazine-1-carboxylate (0.40 mmol) (from Example 2j) in1,4-dioxane (0.5 mL) is added p-TSA monohydrate (1.2 mmol). The reactionmixture is heated at 90° C. overnight. The crude mixture is purified bypreparative LCMS to afford3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)benzyl4-methylpiperazine-1-carboxylate as a TFA salt. ¹H NMR (400 MHz, CD₃OD)δ 11.15 (s, 1H), 8.61 (s, 2H), 7.72-7.77 (m, 1H), 7.30-7.38 (m, 3H),7.04-7.07 (m, 1H), 6.95-7.00 (m, 2H), 4.20 (s, 2H), 3.70-4.10 (m, 4H),3.80 (s, 3H), 3.30-3.52 (m, 4H), 2.75 (s, 3H). MS (m/z) (M+1)⁺ 434.2.

Example 6o(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzylamino)-aceticacid tert-butyl ester

(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzylamino)-aceticacid tert-butyl ester can be prepared by the following procedure. Amixture of4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzaldehyde(from Example 5f) (0.02 mol), triethylamine (0.06 mmol) and tert-butylglycine ester (0.04 mmol) in THF (0.1 mL) is stirred at ambienttemperature for 0.5 h in the presence of excess anhydrous Na₂SO₄.NaBH(OAc)₃ (0.1 mmol) is added and the mixture is further stirred for 1h. MeOH is added and the resultant crude mixture is purified bypreparative LCMS to yield the title compound. ¹H NMR (400 MHz, D₂O) δ8.68 (s, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.42 (d,J=9 Hz, 2H), 7.07 (d, J=9.1 Hz, 2H), 4.4 (d, J=5.1 Hz, 2H), 4.34 (s,2H), 3.91 (s, 2H), 3.62 (t, J=4.8 Hz, 2H), 3.34 (m, 4H), 1.46 (s, 9H),1.34 (t, J=7.3, Hz, 6H). MS (m/z) (M+1)⁺ 506.3.

Example 6p[4-(2-Dimethylamino-ethyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[4-(2-Dimethylamino-ethyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be prepared by the following procedure. A mixture of4-(2-dimethylamino-ethyl)-phenylamine (0.1 mmol), p-TSA (0.05 mmol) and2-chloro-5-(4-methoxy-phenyl)-pyrimidine (from Example 4c) (0.1 mmol) inNMP (0.2 mL) is heated by microwave at 215° C. for 15 min to afford thecrude mixture which is purified by preparative LCMS to yield the titlecompound. ¹H NMR (400 MHz, CDCl₃) δ 12.1 (s, 1H), 11.5 (s, 1H), 8.67 (s,2H), 7.63 (d, J=8.3 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H), 7.19 (d, J=8.3 Hz,2H), 7.04 (d, J=8.7 Hz, 2H), 3.87 (s, 3H), 3.01 (m, 2H), 2.82 (s, 6H),2.09 (m, 2H). MS (m/z) (M+1)⁺ 349.2.

Example 6q3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acid

3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acidcan be prepared by the following procedure. 3-(4-Amino-phenyl)-propionicacid (1.0 mmol), p-TSA (0.25 mmol) and2-chloro-5-(4-methoxy-phenyl)-pyrimidine (from Example 4c) (1.0 mmol)are dissolved in NMP (2 mL) and heated by microwave at 215° C. for 15min to afford the crude3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic acid.MS (m/z) (M+1)⁺ 350.2.

Example 6r[4-(3-Diethylamino-propyl)-phenyl]-[5-(4-m[ethoxy-phenyl)-pyrimidin-2-yl]-amine

4-(3-Diethylamino-propyl)-phenyl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be prepared by the following procedure. Diethylamine (10 mmol), EDC(25 mmol) and DMAP (0.1 mmol) are dissolved in dichloromethane (3 mL)and added to the crude3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionic aciddissolved in NMP (from example 5ao) at rt. After 3 h, sat. aq NH₄Cl isadded and the mixture is extracted with EtOAc. The combined extracts aredried over anhydrous Na₂SO₄ and solvent is removed. Purification bypreparative HPLC yieldsN,N-diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide.

N,N-Diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide(0.1 mmol) is heated at reflux with lithium aluminum hydride in THF (1.0M, 1.0 mmol) for 4 h. MeOH is added at rt to quench the reaction.Purification by preparative LCMS affords the title compound. ¹H NMR (400MHz, CDCl₃) δ 12.4 (s, 1H), 8.62 (s, 2H), 8.59 (s, 1H), 7.61 (d, J=8.3Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.02 (d, J=8.6Hz, 2H), 3.86 (s, 3H), 3.1 (m, 4H), 3.96 (s, 1H), 3.0 (m, 2H), 2.71 (t,J=7.2, 2H), 2.06 (m, 2H), 1.27 (t, J=7.3 Hz, 6H). MS (m/z) (M+1)⁺ 391.2.

Example 6s Synthesis of4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzoicacid

4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzoicacid can be prepared by the following procedure.(5-Bromo-pyrimidin-2-yl)-[4-(2-diethylamino-ethoxy)-phenyl-amine (fromExample 3a) (1 mmol), Pd(PPh₃)₄ (0.1 mmol),3-fluoro-4-methoxycarbonyl-benzeneboronic acid (1.5 mmol) are dissolvedin 2 mL of DMF. After purging with nitrogen, Na₂CO₃ (0.4 mL of a 5M aqsolution) is added and the mixture is heated in the microwave at 120° C.for 20 min. The resultant mixture is diluted with EtOAc and water. Afterextraction with EtOAc and drying with anhydrous Na₂SO₄, the solvent isremoved to afford the crude mixture which is purified by preparativeHPLC to yield4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzoicacid. MS (m/z) (M+1)⁺ 425.2.

Example 6t Synthesis of tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)acetate

Tert-butyl2-(4-(2-(4-(2-(diethylamino)ethoxy)phenylamino)pyrimidin-5-yl)-2-fluorobenzamido)-acetatecan be prepared by the following procedure.4-{2-[4-(2-diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-2-fluoro-benzoicacid (from Example 5) (0.05 mmol), HATU (0.075 mmol), amino-acetic acidtert-butyl ester (0.05 mmol) and diisopropylethylamine (0.1 mmol) in DMF(0.1 mL) are stirred at rt for 2 h. Purification by preparative LCMSaffords the title compound. ¹H NMR (400 MHz, CDCl₃) δ 11.8 (s, 1H), 10.6(s, 1H), 8.72 (s, 2H), 8.25 (t, J=8.1 Hz, 1H), 7.6 (d, J=4.1 Hz, 2H),7.41 (t, J=8.1 Hz, 1H), 7.28 (m, 1H), 6.95 (d, J=8.7 Hz, 2H), 4.52 (s,2H), 4.2 (d, J=4.6 Hz, 2H), 3.5 (s, 2H), 3.3 (m, 4H), 2.73 (m, 2H), 1.52(s, 9H), 1.46 (t, J=7.1 Hz, 6H). MS (m/z) (M+1)⁺ 538.3.

Example 6uN′-(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoyl)-hydrazinecarboxylicacid tert-butyl ester

N′-(4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoyl)-hydrazinecarboxylicacid tert-butyl ester can be prepared by the following procedure.4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoicacid (from Example 5o) (0.3 mmol), hydrazinecarboxylic acid tert-butylester (0.36 mmol), EDC (0.42 mmol) and DMAP (0.03 mmol) in DMF:THF(0.5:0.5 mL) are stirred at rt for 1 h. The resultant mixture is dilutedwith EtOAc and water. After further extraction with EtOAc and drying ofthe combined organic phases with anhydrous Na₂SO₄, the solvent isremoved to afford the crude mixture which is purified by silicachromatography (10% MeOH in DCM) to yield the title compound. ¹H NMR(400 MHz, CDCl₃) δ 8.6 (s, 2H), 7.89 (d, J=8.3 Hz, 1H), 7.56 (d, J=8.3Hz, 2H), 7.51 (d, J=9 Hz, 2H), 7.22 (s, 1H), 6.92 (d, J=9 Hz, 2H), 4.1(t, J=6.2 Hz, 2H), 3.02 (s, 1H), 2.91 (t, J=6.2 Hz, 2H), 2.68 (dd,J=14.3, 7.1 Hz, 4H), 1.51 (s, 9H), 1.1 (t, J=7.1 Hz, 6H). MS (m/z)(M+1)⁺ 521.2.

Example 6v4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-N-phenoxy-benzamide

4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-N-phenoxy-benzamidecan be prepared by the following procedure.4-{2-[4-(2-Diethylamino-ethoxy)-phenylamino]-pyrimidin-5-yl}-benzoicacid from (Example 5o) (0.03 mmol), o-phenyl-hydroxylamine (0.04 mmol),HATU (0.04 mmol) and diisopropylethylamine (0.1 mmol) in DMF (0.1 mL)are stirred at rt for 1 h. The resultant mixture is purified bypreparative LCMS to yield title compound. ¹H NMR (400 MHz, CDCl₃) δ 9.28(s, 1H), 8.68 (d, J=7.2 Hz, 2H), 8.15 (d, J=8.3 Hz, 1H), 8.01 (d, J=8.3Hz, 1H), 7.57-7.6 (m, 5H), 7.35 (dd, J=8.6, 7.5 Hz, 1H), 7.2 (d, J=7.8Hz, 1H), 7.08 (t, J=7.3 Hz, 1H), 6.91 (dd, J=8.9, 5.3 Hz, 2H), 4.39 (dd,J=9.1, 4.6 Hz, 2H), 3.96 (s, 1H), 3.52 (dd, J=8.7, 3.7 Hz, 2H), 3.3 (m,4H), 1.39 (dt, J=7.3, 1.3 Hz, 6H). MS (m/z) (M+1)⁺ 498.2.

Example 6w 5-(4-methoxyphenyl)-N-(3-nitrophenyl)pyrimidin-2-amine

5-(4-methoxyphenyl)-N-(3-nitrophenyl)pyrimidin-2-amine can be preparedby the following procedure. 2-Chloro-5-(4-methoxy-phenyl)-pyrimidine(3.0 mmol) (from Example 4c), 3-nitroaniline (3.0 mmol) and p-TSA (0.9mmol) are dissolved in NMP (3 mL) and heated at 215° C. for 15 min bymicrowave. The reaction mixture is partitioned with NaHCO₃/EtOAc. Theorganic layer is washed with brine, dried over magnesium sulfate,filtered and the solvent is removed. The crude product is purified bysilica chromatography with hexanes:EtOAc (2:1) as the eluant (31%). MS(m/z) (M+1)⁺ 323.2.

Example 6x N1-(5-(4-methoxyphenyl)pyrimidin-2-yl)benzene-1,3-diamine

N1-(5-(4-methoxyphenyl)pyrimidin-2-yl)benzene-1,3-diamine can beprepared by the following procedure. To a solution5-(4-methoxyphenyl)-N-(3-nitrophenyl)pyrimidin-2-amine (0.9 mmol) (fromExample 5au) in EtOH (50 mL) is added Pd (10% on carbon, 50% wet, 10%weight). The reaction vessel is evacuated and backfilled with hydrogen.The contents are stirred under a hydrogen atmosphere for 8 h, filteredthrough celite and reduced to dryness (70%). MS (m/z) (M+1)⁺ 293.2.

Example 6vN-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamide

N-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-4-methylpiperazine-1-carboxamidecan be prepared by the following procedure. To a solution ofN1-(5-(4-methoxyphenyl)pyrimidin-2-yl)benzene-1,3-diamine (0.34 mmol)(From Example 5av) in THF (7 mL) are added diisopropylethylamine (0.75mmol) and triphosgene (0.10 mmol). After stirring for 30 min at rt,1-methylpiperazine (1.02 mmol) is added and stirring is continued for 1h. The reaction is partitioned between dichloromethane and water. Theorganic layer is washed with brine, dried over magnesium sulfate,filtered and the solvent is removed. The crude product is crystallizedfrom dichloromethane to afford the desired product as a whitecrystalline solid (50%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.76(s, 2H), 8.49 (s, 1H), 7.83 (t, J=2.0 Hz, 1H), 7.64 (d, J=8.4 Hz, 2H),7.37 (d, J=7.0 Hz, 1H), 7.13 (t, J=8.0 Hz, 1H), 7.05 (d, J=7.0 Hz, 1H),7.04 (d, J=8.0 Hz, 2H), 3.80 (s, 3H), 3.44 (bs, 4H), 2.33 (bs, 4H), 2.22(s, 3H). MS (m/z) (M+1)⁺ 419.2.

Example 6z-1 Methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate

Methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylatecan be prepared by the following procedure. A solution ofmethanesulfonic acid2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl ester(10.0 mmol) (from Example 5af) and methyl piperidine-4-carboxylate (50.0mmol) in DMF (60 mL) is heated at 100° C. for 8 h. The reaction iscooled to rt and poured into water (600 mL). The white precipitate isfiltered, washed with water and air dried. The crude precipitate ispurified by silica chromatography with dichloromethane methanol (3%) aseluant (77%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 8.76 (s, 2H),7.67 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H), 7.13 (d, J=8.2 Hz, 2H),7.04 (d, J=8.2 Hz, 2H), 3.80 (s, 3H), 3.60 (s, 3H), 2.86 (bd, J=10.0 Hz,2H), 2.67 (bt, J=8.4, 2H), 2.41 (dt, J=8.4 Hz, 1H), 2.31 (m, 1H), 2.01(bt, J=10.0 Hz, 2H), 1.81 (bd, J=10.0 Hz, 2H), 1.57 (m, 2H). MS (m/z)(M+1)⁺ 447.4.

Example 6z-21-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid hydrochloride

1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylicacid hydrochloride can be prepared by the following procedure. To asolution of methyl1-(4-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenethyl)piperidine-4-carboxylate(3.9 mmol) (from Example 5ay) in methanol:THF:water=3:2:1 (38 mL total)is added LiOH (2.0 mL of a 6N solution) and the mixture is stirred at rtfor 12 h. The reaction is reduced to 50% of its volume, water (100 mL)is added and the contents are neutralized with 3M HCl. The resultingwhite precipitate is filtered, triturated repeatedly with acetonitrile,and dried under vacuum (96%). The white precipitate is suspended inacetonitrile (30 mL) and treated with HCl (3.7 mL of a 4M solution indioxane). After stirring for 1 h the reaction is reduced to dryness anddried under vacuum to yield a bright yellow precipitate (99%). ¹H NMR(400 MHz, DMSO-d₆) δ 10.71 (bs, 1H), 9.76 (s, 1H), 8.78 (s, 2H), 7.75(d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.2 Hz, 2H), 7.04(d, J=8.2 Hz, 2H), 3.80 (2, 3H), 3.57 (m, 2H), 3.21 (m, 2H), 3.01 (m,4H), 2.06 (m, 2H), 1.92 (m, 2H). MS (m/z) (M+1)⁺ 469.1.

Example 7 Example 7a2-(methoxycarbonyl)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate

2-(methoxycarbonyl)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate can be prepared by the followingprocedure. To a flask under nitrogen atmosphere containing dry dioxane(8 mL) are added Pd(OAc)₂ (0.1 mmol), Xantphos (0.12 mmol) followed by2-(methoxycarbonyl)-5-aminophenyl 4-methylpiperazine-1-carboxylate (1mmol) (from Example 2l), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (1.5mmol) (from Example 4c) and KOtBu (1.5 mol). The reaction mixture isheated at 90° C. for 2 h and the crude is purified by preparative LCMSto yield2-(methoxycarbonyl)-5-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl4-methylpiperazine-1-carboxylate (76%). MS (m/z) (M+1)⁺ 478.2.

Example 7b2-(2-Diethylamino-ethoxy)-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid ethyl ester

2-(2-Diethylamino-ethoxy)-5-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzoicacid ethyl ester synthesized by the following procedure. A 15 ml flaskis charged with 5-amino-2-(2-diethylamino-ethoxy)-benzoic acid ethylester (0.19 mmol), 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (0.19 mmol),p-TSA (0.22 mmol) and NMP (2 mL). The flask is evacuated and irradiatedin a microwave oven at 210° C. for 15 min. The reaction mixture isdiluted with water and extracted with DCM (5×50 mL). The organic layeris washed with brine, dried over Na₂SO₄, and concentrated. Purificationby preparative LCMS (ACN gradient 10-70%) affords the title compounds(20%) as TFA salt. ¹HNMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 9.29 (b.s1H), 8.78 (s, 2H), 8.14-8.15 (m, 1H), 7.98-7.95 (m, 1H), 7.66-7.64 (m,2H), 7.21-7.18 (m, 1H), 7.05-7.03 (m, 2H), 4.37-4.35 (m, 2H), 4.28-(q,J=8.0 Hz, 2H), 3.80 (s, 3H), 3.55-3.54 (m, 2H), 3.32-3.27 (m, 4H), 1.32(t, J=8.0 Hz, 3H), 1.24 (t, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 465.2.

Example 7c 2-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)aceticacid

2-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)acetic acid can beprepared by the following procedure. To a mixture of2-chloro-5-(4-methoxy-phenyl)-pyrimidine (1.0 mmol) (from Example 4c)and 2-(3-aminophenyl)acetic acid (1.0 mmol) in 1,4-dioxane (2 mL) isadded p-TSA monohydrate (1.0 mmol). The reaction mixture is heated at90° C. for 5 h. After the reaction is complete, the solvent is removed.The residue is dissolved in EtOAc and washed with water, dried overMgSO₄ and concentrated to afford a pale yellow solid which is used inthe next step without purification. MS (m/z) (M+1)⁺ 336.1.

Example 7d2-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanone

2-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)-1-(4-methylpiperazin-1-yl)ethanonecan be prepared by the following procedure. A mixture of2-(3-(5-(4-methoxyphenyl)pyrimidin-2-ylamino)phenyl)acetic acid (fromExample 5bc) (0.05 mmol), HATU (0.075 mmol), 1-methylpiperazine (0.05mmol) and diisopropylethylamine (0.1 mmol) in DMF (0.5 mL) is stirred atrt for 2 h. Purification with preparative LCMS affords the titlecompound. MS (m/z) (M+1)⁺ 418.2.

Example 7e6-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazol-2-one

6-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazol-2-one can besynthesized by the following procedure. A dry flask charged with6-amino-3H-benzooxazol 2-one (2.03 mmol) (from Example 2n), p-TSA (0.61mmol), 2 5-(4-methoxy-phenyl)-pyrimidin-2-ylamine (2.03 mmol), and NMP(5 mL) is heated by microwave at 210° C. for 15 min. The reactionmixture is diluted with water and extracted with EtOAc (3×20 mL). Theorganic layer is washed with water, brine, dried over Na₂SO₄, andconcentrated. The crude oil is titrated with hexane to afford the titlecompound as an off white solid (40%). ¹HNMR (400 MHz, DMSO-d₆) δ 11.47(s, 1H), 9.79 (s, 1H), 8.78 (s, 2H), 7.94 (b.s. 1H), 7.65 (d, J=2.0 Hz,2H), 7.44-7.41 (m, 3H), 7.05-7.01 (m, 3H), 3.89 (s, 3H). MS (m/z) (M+1)⁺335.2.

Example 7f6-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazole-2-thione

6-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazole-2-thionecan be prepared by the following procedure. A dry flask charged with6-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazol-2-one (0.45mmol) (from Example 5be), Lawesson's reagent (1.8 mmol), and a 5:1mixture of THF:toluene (6 ml) is heated by microwave at 160° C. for 45min. The reaction mixture is diluted with water and extracted with EtOAc(3×20 mL). The organic layer is washed with water, brine, dried overNa₂SO₄, and concentrated. The crude mixture is purified by silicachromatography using a 9:1 mixture DCM:MeOH as eluent to afford6-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazole-2-thione asa yellow solid (48% based on recovered starting material). ¹HNMR (400MHz, DMSO-d₆) δ 10.0 (s, 1H), 8.82 (s, 2H), 8.19 (b.s. 1H), 7.68-7.66(m, 2H), 7.57 (dd, J=2.0 and 8.0 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 7.05(d, J=8.0 Hz, 2H), 3.89 (s, 3H). MS (m/z) (M+1)⁺ 351.2.

Example 7g[2-(4-Isopropyl-piperazin-1-yl)-benzooxazol-6-yl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-amine

[2-(4-Isopropyl-piperazin-1-yl)-benzooxazol-6-yl]-[5-(4-methoxy-phenyl)-pyrimidin-2-yl]-aminecan be synthesized by the following procedure. A dry flask charged with6-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-3H-benzooxazole-2-thione(0.034 mmol) (from example 5bf), N-isopropyl piperazine (1 mL), and THF(0.5 mL) is heated by microwave at 150° C. for 10 min. Purification bypreparative LCMS affords the title compound as TFA salt. ¹HNMR (400 MHz,CD₃OD) δ 8.65 (s, 2H), 8.12 (bs, 1H), 7.55 (d, J=8.0 Hz, 2H), 7.3-7.30(m, 2H), 7.05-7.03 (m, 2H), 5.46 (b.m 2H), 3.84 (s, 3H), 3.67-3.32 (m,5H), 1.43 (d, J=8.0 Hz, 6H). MS (m/z) (M+1)⁺ 445.8.

Example 7h{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-acetaldehyde

{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-acetaldehyde canbe synthesized by the following procedure. Dess-Martin reagent (4.35mmol) is suspended in anhydrous THF (20 mL) and NaHCO₃ (10 mmol) isadded. The suspension is stirred at rt for 15 min then a solution of2-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethanol (fromExample 5ae) (3.11 mmol) in THF (10 mL) is added. The stirring iscontinued for 15 min, after that the reaction mixture is diluted withEtOAc and washed with a 5% NaHCO₃ solution (1×50 mL), brine (1×50 mL),dried over Na₂SO₄, and concentrated to afford a light brown solid. Thecrude is purified by HPLC (ACN 30-90% gradient) to afford{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-acetaldehyde asoff white solid (70%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.75 (s, 1H), 9.67 (s,1H), 8.78 (s, 2H), 7.77 (d, J=8.0 Hz, 2H), 7.65 (d, J=8.0 Hz, 2H), 7.15(d, J=8.0 Hz, 2H), 7.04 (d, J=8.0 Hz, 2H), 3.80 (s, 3H), 3.69 (s, 2H).MS (m/z) (M+1)⁺ 320.2.

Example 7i(R)-1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl)-piperidine-3-carboxylicacid

(R)-1-(2-{4-[5-(4-Methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-ethyl)-piperidine-3-carboxylicacid can be synthesized by the following procedure. To a solution of{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-acetaldehyde (0.31mmol) in DCM (10 mL) (R)-nipecotic acid (0.44 mmol) is added. Thesolution is stirred at rt for 1 h then NaB(OAc)₃H is added at once andthe stirring is continued for an additional hour. The solvent is removedunder reduced pressure and the residue is purified by HPLC (ACN gradient10-90%) to afford the title compound. ¹HNMR (600 MHz, DMSO-d₆) δ 10.43(b.s, 1H), 9.71 (s, 1H), 8.78 (s, 2H), 7.74 (d, J=8.3 Hz, 1H), 7.63 (d,J=8.0 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 3.79 (s,3H), 3.69-3.67 (m, 2H), 3.56-3.53 (m, 2H), 3.29-3.25 (m, 2H), 3.02-2.95(m, 2H), 2.91-2.86 (m, 2H), 2.07-20.4 (m, 1H), 1.91-1.83 (m, 2H). MS(m/z) (M+1)⁺ 433.1.

The exemplary compounds given in Table 1 can be synthesized according tothe conditions described in examples 1-7.

Example 8 Pharmaceutical Compositions Example 8a Parenteral Composition

To prepare a parenteral pharmaceutical composition suitable foradministration by injection, 100 mg of a water-soluble salt of acompound of Formula (A) or Formula (B) is dissolved in DMSO and thenmixed with 10 mL of 0.9% sterile saline. The mixture is incorporatedinto a dosage unit form suitable for administration by injection.

Example 8b Oral Composition

To prepare a pharmaceutical composition for oral delivery, 100 mg of acompound of Formula (A) or Formula (B) is mixed with 750 mg of lactose.The mixture is incorporated into an oral dosage unit, such as a hardgelatin capsule, which is suitable for oral administration.

Example 8c Inhalation Composition

To prepare a pharmaceutical composition for inhalation delivery, 25 mgof a compound of Formula (A) or Formula (B) is mixed with 2 mL of 95%ethanol and 100 mL of 0.9% sodium chloride solution. The mixture isincorporated into an inhalation delivery unit, such as a nebulizer,which is suitable for inhalation administration.

Example 8d Suppository Composition

To prepare a pharmaceutical composition for rectal delivery [such astwelve 1.8 g. cocoa butter base, medicated suppositories containing 300mg of a compound of Formula (A) or Formula (B)], 3.6 g. of a compound ofFormula (A) or Formula (B) is mixed with 18 g. of cocoa butter. Themixture is gently fused and the resulting melt is poured into molds toform suppositories suitable for rectal administration.

Example 9 Functional Assay of c-kit Inhibition

The compounds described herein are tested for inhibition of SCFdependent proliferation using Mo7e cells which endogenously expressc-kit in a 96 well format. Briefly, two-fold serially diluted testcompounds (C_(max)=10 μM) are evaluated for their antiproliferativeactivity on Mo7e cells stimulated with human recombinant SCF. After 48hour incubation at 37° C., cell viability is measured by using a MTTcalorimetric assay from Promega.

Exemplary test compounds are evaluated using the functional assaydescribed above for inhibition of the c-kit receptor. The ability ofcompounds of Formula (A) or Formula (B) to antagonize 50% of thespecified c-kit receptor yields IC₅₀ values for the compounds tested. Incertain embodiments compounds of Formula (A) or Formula (B) have IC₅₀values greater than about 10 μM, while in other embodiments compounds ofFormula (A) or Formula (B) have IC₅₀ values between about 1 μM and about10 μM. In still other embodiments, compounds of Formula (A) or Formula(B) have IC₅₀ values between about 0.1 μM and about 1 μM. While in evenfurther embodiments, compounds of Formula (A) or Formula (B) have IC₅₀values less than about 0.1 μM.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference for allpurposes.

1. A compound having the structure of Formula (1) or Formula (46):

wherein: Ar is a group comprising a moiety selected from an optionallysubstituted five-membered aromatic heterocycle, an optionallysubstituted five-membered aromatic carbocycle, an optionally substitutedsix-membered aromatic heterocycle, and a substituted, optionally furthersubstituted phenyl; Q is a group comprising a non-aromatic tertiaryamine or a non-aromatic secondary amine, with the proviso that Q is not—NR_(a)R_(b) or —SO₂NR_(a)R_(b); wherein each of R_(a) and R_(b) isindependently H or C₁₋₆alkyl optionally substituted by mono- or di-alkyl(C₁₋₆) amino; each R₁ is independently an optionally substituted moietyselected from -L₁-H or -L₁-C₁₋₆alkyl; wherein L₁ is selected from abond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, C(O)NH(CR″₂)₁₋₆C(O)O—, —C(O)NR″NR″C(O)O—, and —S(O)NH—; each R″is independently H, OH, halogen, C₁₋₆alkyl, substituted C₁₋₆alkyl,C₁₋₆alkoxy, halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, orheteroaryl; or any two adjacent R₁ groups together may form, anoptionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or arylring; R₅ is H or C₁₋₆alkyl; or a pharmaceutically acceptable salt orpharmaceutically acceptable N-oxide thereof.
 2. The compound of claim 1,wherein the Ar is a group comprising a substituted, optionallyfurther-substituted six-membered aromatic heterocycle.
 3. The compoundof claim 1, wherein said optional substituents are selected fromhalogen, OH, halogen, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₄alkoxy, aryl, haloaryl, or heteroaryl.
 4. The compound of claim1, wherein Ar is selected from the group consisting of


5. The compound of claim 1, wherein Q is selected from the groupconsisting of


6. The compound of claim 5, wherein Ar is selected from the groupconsisting of


7. (canceled)
 8. The compound of claim 1, wherein the compound havingthe structure of Formula (1) is selected from Formula (2), Formula (3),or Formula (44):

wherein: M is selected from the group consisting of H, OH, SH, NO₂, CN,NR″₂, and an optionally substituted moiety selected from -L₇-alkyl,-L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl, -L₇-aryl,-L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇ is selected from abond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —OC(O)—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—,—C(O)NR″Y¹C(O)O—, —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—,—CR″₂NR″WO—, —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ isoptionally substituted arylene or optionally substituted heteroarylene;wherein said optional substituents are selected from halogen, OH,C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy; provided thatM is not H in Formula (2); each R″ is independently H, OH, halogen,C₁₋₆alkyl, substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, halo aryl, or heteroaryl; each X is independentlyselected from N or CR₂, provided that at least one but no more than 2Xgroups are N; each R₂ is independently selected from the groupconsisting of H, OH, halogen, and an optionally substituted moietyselected from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,-L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂ isselected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)—,—C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents areselected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, andhalo-C₁₋₆alkoxy; or any two adjacent R₂ groups together may form anoptionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or arylring; or a pharmaceutically acceptable salt or pharmaceuticallyacceptable N-oxide thereof.
 9. The compound of claim 1, wherein thecompound having the structure of Formula (46) is selected from Formula(47), Formula (48), or Formula (49):

wherein: M is selected from the group consisting of H, OH, SH, NO₂, CN,NR″₂, and an optionally substituted moiety selected from -L₇-alkyl,-L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl, -L₇-aryl,-L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇ is selected from abond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —OC(O)—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—,—C(O)NR″Y¹C(O)O—, —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—,—CR″₂NR″WO—, —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ isoptionally substituted arylene or optionally substituted heteroarylene;wherein said optional substituents are selected from halogen, OH,C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy; provided thatM is not H in Formula (47); each R″ is independently H, OH, halogen,C₁₋₆alkyl, substituted C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl,halo-C₁₋₆alkoxy, aryl, haloaryl, or heteroaryl; each X is independentlyselected from N or CR₂, provided that at least one but no more than 2Xgroups are N; each R₂ is independently selected from the groupconsisting of H, OH, halogen, and an optionally substituted moietyselected from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,-L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂ isselected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents areselected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, andhalo-C₁₋₆alkoxy; or any two adjacent R₂ groups together may form anoptionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or arylring; or a pharmaceutically acceptable salt or pharmaceuticallyacceptable N-oxide thereof.
 10. The compound of any of claims 1-4, 8,and 9, wherein Q is selected from the group consisting of


11. (canceled)
 12. (canceled)
 13. The compound of any of claims 8 or 9,wherein each R₂ is H.
 14. A method for modulating the activity of ac-kit kinase receptor comprising contacting the c-kit kinase receptorwith a compound having the structure of Formula (1) or Formula (46) ofclaim
 1. 15. A method of treating a disease in an animal in whichmodulation of c-kit receptor activities can prevent, inhibit orameliorate the pathology and/or symptomology of the diseases, whichmethod comprises administering to the animal a therapeutically effectiveamount of a compound having the structure of Formula (1) or Formula (46)of claim
 1. 16. A method for making the compound of claim 1 having thestructure of Formula (1), comprising admixing a compound of structure:

with a compound having the structure:

to yield a compound having the structure of Formula (C):

and further admixing the compound having the structure of Formula (C)with a compound of structure: ArB(OH)₂.
 17. (canceled)
 18. A method ofclaim 15, wherein the compound having a structure according to Formula(1) has a structure according to Formula (23), Formula (24), Formula(45), Formula (50), Formula (51), or Formula (52):

wherein: M is selected from the group consisting of H, OH, SH, NO₂, CN,NR″₂, and an optionally substituted moiety selected from -L₇-alkyl,-L₇-cycloalkyl, -L₇-heteroalkyl, -L₇-haloalkyl, -L₇-aryl,-L₇-heterocycloalkyl, and -L₇-heteroaryl; wherein L₇ is selected from abond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—, —S(O)—,—S(O)₂—, —OC(O)—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —CR″₂NR″CR″₂C(O)O—,—C(O)NR″Y¹C(O)O—, —C(O)NR″NR″C(O)O—, —S(O)NH—, —C(O)NR″CR″₂C(O)W—,—CR″²NR″WO—, —CR″₂NR″Y¹C(O)O—, and —C(O)NR″O—; W is C₁₋₆alkylene; Y¹ isoptionally substituted arylene or optionally substituted heteroarylene;wherein said optional substituents are selected from halogen, OH,C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl and halo-C₁₋₆alkoxy; provided thatM is not H in Formula (23) or Formula (50); each R″ is independently H,OH, halogen, C₁₋₄alkyl, substituted C₁₋₆-allyl, C₁₋₆alkoxy,halo-C₁₋₆alkyl, halo-C₁₋₆alkoxy, aryl, haloaryl, or heteroaryl; each Xis independently selected from N or CR₂, provided that at least one butno more than 2X groups are N; each R₂ is independently selected from thegroup consisting of H, OH, halogen, and an optionally substituted moietyselected from -L₂-alkyl, -L₂-cycloalkyl, -L₂-heteroalkyl, -L₂-haloalkyl,-L₂-aryl, -L₂-heterocycloalkyl, and -L₂-heteroaryl; wherein L₂ isselected from a bond, —O—, —NH—, —S—, —C(O)—, —C(S)—, —C(O)O—, —C(O)NH—,—S(O)—, —S(O)₂—, —C(O)NR″(CR″₂)₁₋₆C(O)O—, —OC(O)—, —CR″₂NR″CR″₂C(O)O—,—C(O)NR″NR″C(O)O—, and —S(O)NH—; wherein said optional substituents areselected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy, halo-C₁₋₆alkyl, andhalo-C₁₋₆alkoxy; or any two adjacent R₂ groups together may form anoptionally substituted 5 to 8-membered heterocyclic, cycloalkyl, or arylring; each of R₃ and R₄ is independently an optionally substitutedmoiety selected from -Z, -L₃-Z, -L₃-H, -L₃-alkyl, -L₃-cycloalkyl,-L₃-heteroalkyl, -L₃-haloalkyl, -L₃-aryl, -L₃-heterocycloalkyl, and-L₃-heteroaryl; wherein L₃ is selected from a bond, —C(S)—, —C(O)O—,—C(O)NR′″—, —(CR″₂)₁₋₆—, —CR′″₂S(O)—, —CR′″₂S(O)₂—, —CR′″₂S(O)NR′″—,—CR′″₂C(O)NR′″—, —(CR′″₂)₁₋₆NR′″—, —(CR′″₂)₁₋₆O—, —(CR′″₂)₁₋₆C(O)O—,—Y²C(O)O—, and an optionally substituted C₁₋₆alkylene; wherein saidoptional substituents are selected from halogen, —OH, ═O, —Y³,C₁₋₆alkyl, C₁₋₆alkoxy, halogen or OH substituted C₁₋₆alkyl, halogen orOH substituted C₁₋₆alkoxy, —(CR′″₂)₁₋₆C(O)OR₆, —C(O)NR′″₂, —C(O)R₆, or—C(O)OR₆; Y² is an optionally substituted cycloalkyl ring or optionallysubstituted non-aromatic heterocyclic ring; wherein said optionalsubstituents are selected from C₁₋₆alkyl, halogen, —OH, ═O, and —CN. Y³is optionally substituted aryl, optionally substituted heteroaryl,optionally substituted cycloalkyl, or optionally substitutednon-aromatic heterocycle; wherein said optional substituents areselected from C₁₋₆alkyl, halogen, —OH, ═O and CN. Z is —H, —OH, —CN,—COOR′″, —NR′″₂, or —C≡CR′″; each R′″ is independently H, alkyl, orsubstituted alkyl; or two R′″ together may form a 3-6 memberedcycloalkyl or heterocyclic ring; or R₃ and R₄ taken together with the Natom to which they are attached may form an optionally substituted 3 to8-membered heterocyclic ring; wherein said optional substituents areselected from halogen, —OH, ═O, —Y³, C₁₋₄alkyl, C₁₋₆alkoxy, halogen orOH substituted C₁₋₆alkyl, halogen or OH substituted C₁₋₆alkoxy,—(CR′″₂)₁₋₆Y⁴, —(CR′″₂)₁₋₆OR₆, —C(O)NR′″R₆, —C(O)OR₆, —OR₆,—NR′″C(O)OR₆, —NR′″C(O)R₆, —(CR′″₂)₁₋₆C(O)OR₆, —(CR′″₂)₁₋₆NR′″C(O)OR₆,—(CR′″₂)₁₋₆R₇R₈, —S(O)₂NR′″₂, —C(O)R₆, —OC(O)R₆, —NR₇R₈,—(CR′″₂)₁₋₆C(O)NR₇R₈, —S(O)₂R_(A), or —C(O)R_(A); Y⁴ is aryl,heteroaryl, cycloalkyl, or non-aromatic heterocycle; R_(A) is selectedfrom —NH₂, —NEt₂, and —NH(CH₂)₁₋₆OH; R₆ is H, alkyl, substituted alkyl,cycloalkyl, non-aromatic heterocycle, aryl, or heteroaryl; each of R₇and R₈ is independently H, OH, halogen, C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkyl, or halo-C₁₋₆alkoxy; or R₇ and R₈ taken together with theN atom to which they are attached may form a 3 to 6-memberedheterocyclic ring; T₁ is an optionally substituted moiety selected from-L₄-, -alkylene-L₄-, -L₄-alkylene-, -L₄-cycloalkylene-,-L₄-heteroalkylene-, -L₄-haloalkylene-, -L₄-arylene-,-L₄-heteroarylene-, and -L₄-heterocycloalkylene-; wherein L₄ is selectedfrom a bond, —O—, —NH—, —S—, —CR″₂—, —NR′″C(O)—, —C(O)—, —C(S)—,—C(O)O—, —C(O)NR′″—, —S(O)—, —S(O)₂—, —OC(O)—, —C(O)NR′″(CR″₂)₁₋₆C(O)O—,—C(O)NR′″(CR″₂)₁₋₆C(O)—, —CR″₂NR′″CR″₂C(O)O—, —C(O)NR′″NR′″C(O)O—,—C(O)NR′″(CR″₂)₁₋₆—, —CR″₂C(O)—, and —S(O)NH—; wherein said optionalsubstituents are selected from halogen, OH, C₁₋₆alkyl, C₁₋₆alkoxy,halo-C₁₋₆alkyl, halo-C₁₋₄alkoxy, aryl, haloaryl, and heteroaryl; or apharmaceutically acceptable salt or pharmaceutically acceptable N-oxidethereof.